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Sneeze

A sneeze (also known as sternutation) is a semi-autonomous, convulsive expulsion of air from the lungs through the nose and mouth, usually caused by foreign particles irritating the nasal mucosa. A sneeze expels air forcibly from the mouth and nose in an explosive, spasmodic involuntary action. This action allows for mucus to escape through the nasal cavity. Sneezing is possibly linked to sudden exposure to bright light, sudden change (fall) in temperature, breeze of cold air, a particularly full stomach, exposure to allergens, or viral infection. Because sneezes can spread disease through infectious aerosol droplets, it is recommended to cover ones mouth and nose with the forearm, the inside of the elbow, a tissue or a handkerchief while sneezing. In addition to covering the mouth, looking down is also recommended in order to change the direction of the droplets spread and avoid high concentration in the human breathing heights. The function of sneezing is to expel mucus containing foreign particles or irritants and cleanse the nasal cavity. During a sneeze, the soft palate and palatine uvula depress while the back of the tongue elevates to partially close the passage to the mouth, creating a venturi (similar to a carburetor) due to Bernoullis principle so that air ejected from the lungs is accelerated through the mouth and thus creating a low pressure point at the back of the nose. This way air is forced in through the front of the nose and the expelled mucus and contaminants are launched out the mouth. Sneezing with the mouth closed does expel mucus through the nose but is not recommended because it creates a very high pressure in the head and is potentially harmful. Sneezing cannot occur during sleep due to REM atonia – a bodily state where motor neurons are not stimulated and reflex signals are not relayed to the brain. Sufficient external stimulants, however, may cause a person to wake from sleep to sneeze, but any sneezing occurring afterwards would take place with a partially awake status at minimum. Description Sneezing typically occurs when foreign particles or sufficient external stimulants pass through the nasal hairs to reach the nasal mucosa. This triggers the release of histamines, which irritate the nerve cells in the nose, resulting in signals being sent to the brain to initiate the sneeze through the trigeminal nerve network. The brain then relates this initial signal, activates the pharyngeal and tracheal muscles and creates a large opening of the nasal and oral cavities, resulting in a powerful release of air and bioparticles. The powerful nature of a sneeze is attributed to its involvement of numerous organs of the upper body – it is a reflexive response involving the face, throat, and chest muscles. Sneezing is also triggered by sinus nerve stimulation caused by nasal congestion and allergies. The neural regions involved in the sneeze reflex are located in the brainstem along the ventromedial part of the spinal trigeminal nucleus and the adjacent pontine-medullary lateral reticular formation. This region appears to control the epipharyngeal, intrinsic laryngeal and respiratory muscles, and the combined activity of these muscles serve as the basis for the generation of a sneeze.The sneeze reflex involves contraction of a number of different muscles and muscle groups throughout the body, typically including the eyelids. The common suggestion that it is impossible to sneeze with ones eyes open is, however, inaccurate. Other than irritating foreign particles, allergies or possible illness, another stimulus is sudden exposure to bright light – a condition known as photic sneeze reflex (PSR). Walking out of a dark building into sunshine may trigger PSR, or the ACHOO (autosomal dominant compulsive helio-ophthalmic outbursts of sneezing) syndrome as its also called. The tendency to sneeze upon exposure to bright light is an autosomal dominant trait and affects 18-35% of the human population. A rarer trigger, observed in some individuals, is the fullness of the stomach immediately after a large meal. This is known as snatiation and is regarded as a medical disorder passed along genetically as an autosomal dominant trait. Epidemiology While generally harmless in healthy individuals, sneezes spread disease through the infectious aerosol droplets, commonly ranging from 0.5 to 5 µm. A sneeze can produce 40,000 droplets. To reduce the possibility of thus spreading disease (such as the flu), one holds the forearm, the inside of the elbow, a tissue or a handkerchief in front of ones mouth and nose when sneezing. Using ones hand for that purpose has recently fallen into disuse as it is considered inappropriate, since it promotes spreading germs through human contact (such as handshaking) or by commonly touched objects (most notably doorknobs). Until recently, the maximum visible distance over which the sneeze plumes (or puffs) travel was observed at 0.6 metres (2.0 ft), and the maximum sneeze velocity derived was 4.5 m/s (about 10 mph). In 2020, sneezes were recorded generating plumes of up to 8 meters (26 ft). Prevention Proven methods to reduce sneezing generally advocate reducing interaction with irritants, such as keeping pets out of the house to avoid animal dander; ensuring the timely and continuous removal of dirt and dust particles through proper housekeeping; replacing filters for furnaces and air-handling units; air filtration devices and humidifiers; and staying away from industrial and agricultural zones. Tickling the roof of the mouth with the tongue can stop a sneeze. Some people, however, find sneezes to be pleasurable and would not want to prevent them.Holding in sneezes, such as by pinching the nose or holding ones breath, is not recommended as the air pressure places undue stress on the lungs and airways. One computer simulation suggests holding in a sneeze results in a burst of air pressure of 39 kPa, approximately 24 times that of a normal sneeze. History In Ancient Greece, sneezes were believed to be prophetic signs from the gods. In 401 BC, for instance, the Athenian general Xenophon gave a speech exhorting his fellow soldiers to fight against the Persians. A soldier underscored his conclusion with a sneeze. Thinking that this sneeze was a favorable sign from the gods, the soldiers were impressed. Another divine moment of sneezing for the Greeks occurs in the story of Odysseus. His waiting wife Penelope, hearing Odysseus may be alive, says that he and his son would take revenge on the suitors if he were to return. At that moment, their son sneezes loudly and Penelope laughs with joy, reassured that it is a sign from the gods (Odyssey 17: 541-550). It may be because this belief survived through the centuries, that in certain parts of Greece today, when someone is asserting something and the listener sneezes promptly at the end of the assertion, the former responds "bless you and I am speaking the truth", or "bless you and here is the truth" ("γεια σου κι αλήθεια λέω", ya sou ki alithia leo, or "γεια σου και να κι η αλήθεια", ya sou ke na ki i alithia). A similar practice is also followed in India. If either the person just having made a not most obvious statement in Flemish, or some listener sneezes, often one of the listeneners will say "It is beniesd", literally "Its sneezed upon", as if a proof of truth – usually self-ironically recalling this old superstitious habit, without either suggesting doubt or intending an actual confirmation, but making any apology by the sneezer for the interruption superfluous as the remark is received by smiles.In Europe, principally around the early Middle Ages, it was believed that ones life was in fact tied to ones breath – a belief reflected in the word "expire" (originally meaning "to exhale") gaining the additional meaning of "to come to an end" or "to die". This connection, coupled with the significant amount of breath expelled from the body during a sneeze, had likely led people to believe that sneezing could easily be fatal. Such a theory could explain the reasoning behind the traditional English phrase, "God bless you", in response to a sneeze, the origins of which are not entirely clear (see "Traditional Responses To A Sneeze" below for alternative explanations). Sir Raymond Henry Payne Crawfurd, for instance, the registrar of the Royal College of Physicians, in his 1909 book, "The Last Days of Charles II", states that, when the controversial monarch was on his deathbed, his medical attendants administered a concoction of cowslips and extract of ammonia to promote sneezing. However, it is not known if this promotion of sneezing was done to hasten his death (as coup de grâce) or as an ultimate attempt at treatment. In certain parts of Eastern Asia, particularly in Chinese culture, Korean culture, Japanese culture and Vietnamese culture, a sneeze without an obvious cause was generally perceived as a sign that someone was talking about the sneezer at that very moment. This can be seen in the Book of Songs (a collection of Chinese poems) in ancient China as early as 1000 BC, and in Japan this belief is still depicted in present-day manga and anime. In China, Vietnam, South Korea, and Japan, for instance, there is a superstition that if talking behind someones back causes the person being talked about to sneeze; as such, the sneezer can tell if something good is being said (one sneeze), someone is thinking about you (two sneezes in a row), even if someone is in love with you (three sneezes in a row) or if this is a sign that they are about to catch a cold (multiple sneezes).Parallel beliefs are known to exist around the world, particularly in contemporary Greek, Slavic, Celtic, English, French, and Indian cultures. Similarly, in Nepal, sneezers are believed to be remembered by someone at that particular moment.In English, the onomatopoeia for sneezes is usually spelled achoo and it is similar to that of different cultures. Culture In Indian culture, especially in northern parts of India, Bengali (Bangladesh and Bengal of India) culture and also in Iran, it has been a common superstition that a sneeze taking place before the start of any work was a sign of impending bad interruption. It was thus customary to pause in order to drink water or break any work rhythm before resuming the job at hand in order to prevent any misfortune from occurring. Contrarily, in Polish culture, especially in the Kresy Wschodnie borderlands, a popular belief persists that sneezes may be an inauspicious sign that, depending on the local version, either someone unspecified or ones mother-in-law speaks ill of the person sneezing at that moment. In other regions, however, this superstition concerns hiccups rather than sneezing. As with other Catholic countries, such as Mexico, Italy, or Ireland, the remnants of pagan culture are fostered in Polish peasant idiosyncratic superstitions. The practice among Islamic culture, in turn, has largely been based on various prophetic traditions and the teachings of the prophet Muhammad. An example of this is Al-Bukhaaris narrations from Abu Hurayrah that Muhammad once said: When one of you sneezes, let him say, "Al-hamdu-Lillah" (Praise be to God), and let his brother or companion say to him, "Yarhamuk Allah" (May God have mercy on you). If he says, "Yarhamuk-Allah", then let [the sneezer] say, "Yahdeekum Allah wa yuslihu baalakum" (May God guide you and rectify your condition). Verbal responses In English-speaking countries, one common verbal response to another persons sneeze is "[May God] bless you". Another less common verbal response in the United States and Canada to anothers sneeze is "Gesundheit", which is a German word that means, appropriately, "good health". Several hypotheses exist for why the custom arose of saying "bless you" or "God bless you" in the context of sneezing: Some say it came into use during the plague pandemics of the 14th century. Blessing the individual after showing such a symptom was thought to prevent possible impending death due to the lethal disease. In Renaissance times, a superstition was formed claiming ones heart stopped for a very brief moment during the sneeze; saying bless you was a sign of prayer that the heart would not fail. It has also been stated that one says "(God) bless you" so that one does not catch the flu, cold, or any other forms of sickness.Other cultures have similar traditions: In China, after a person sneezes they often say "百岁!" which translates to "may you live one hundred years!" the pronunciation is similar to "bless you" in English. pronunciation: [Bai Sui] In Iran, it is common to respond to sneezing with the Persian phrase عافیت باشه âfiyat bâše, which translates to "health", similar to common European expressions. Indian culture is to respond with Krishna, similar to a blessing in western cultures. In Italy after a person sneezes the people present respond with the word "salute" (meaning: health). The louder the sneeze the more emphatic the response. In Slovakia, after a person sneezes, it is proper to say "Na zdravie!" which means "For health!"; a proper response should be "Ďakujem" which means "Thanks". This is also the case in Finland where "terveydeksi" means "for health". Likewise in Russian or Ukrainian, "будь здоров" (bud zdorov), translates as "be healthy". In Tamil, a reciprocation to someones sneeze is "ஆயுசு நூறு" (aa-yu-su noo-ru) or "ஆயுள் நூறு" (aa-yul noo-ru) which, in direct translation, means "100 years-long life". It is a particularly endearing expression often used by elderly when a young child sneezes, wishing upon them good health, as a sort of blessing. Some may say "Dheergaiyish", meaning "may you live long", but that is more closely related to Sanskrit. In Turkey, after a person sneezes, it is proper to say "Çok yaşa" which means "Live long"; a proper response should be "Sen de gör" which means "May you see too [that I lived long enough]". In Telugu, a reciprocation to someones sneeze is "chiranjeeva sataish" (చిర౦జీవ) which means "may you live long" (from Sanskrit). In Japanese and Chinese entertainment, such as anime or dramas, a characters sneeze usually means that someone is talking about the character. In the Netherlands and Flanders, the usual verbal response is "Gezondheid!" which has the same meaning as the also occasionally used German word "Gesundheit!". This is usually met with a "Dankjewel" as a response, which means "Thank you". In Sweden, Norway and Denmark after a person sneezes, it is proper to say "Prosit", which has latin roots, and loosely translates to "Be well" or "May it do you good". Sexuality Some people may sneeze during the initial phases of sexual arousal. Doctors suspect that the phenomenon might arise from a case of crossed wires in the autonomic nervous system, which regulates a number of functions in the body, including "waking up" the genitals during sexual arousal. The nose, like the genitals, contains erectile tissue. This phenomenon may prepare the vomeronasal organ for increased detection of pheromones.A sneeze has been compared to an orgasm, since both orgasms and sneeze reflexes involve tingling, bodily stretching, tension and release. On this subject, sexologist Vanessa Thompson from the University of Sydney states, "Sneezing and orgasms both produce feel-good chemicals called endorphins but the amount produced by a sneeze is far less than an orgasm."According to Dr. Holly Boyer from the University of Minnesota, there is a pleasurable effect during a sneeze, where she states, "the muscle tension that builds up in your chest causes pressure, and when you sneeze and the muscles relax, it releases pressure. Anytime you release pressure, it feels good...Theres also some evidence that endorphins are released, which causes your body to feel good". Endorphins induce the brains reward system, and because sneezes occur in a quick burst, so does the pleasure. In non-humans Sneezing is not confined to humans or even mammals. Many animals including cats, dogs, chickens and iguanas sneeze. African wild dogs use sneezing as a form of communication, especially when considering a consensus in a pack on whether or not to hunt. Some breeds of dog are predisposed to reverse sneezing. See also Cough Rhinitis Seizure Snatiation Sniffle References Further reading External links The dictionary definition of sneeze at Wiktionary Media related to Sneezing at Wikimedia Commons

Brain death

Brain death is the permanent, irreversible, and complete loss of brain function which may include cessation of involuntary activity necessary to sustain life. It differs from persistent vegetative state, in which the person is alive and some autonomic functions remain. It is also distinct from comas as long as some brain and bodily activity and function remain, and it is also not the same as the condition locked-in syndrome. A differential diagnosis can medically distinguish these differing conditions. Brain death is used as an indicator of legal death in many jurisdictions, but it is defined inconsistently and often confused by the public. Various parts of the brain may keep functioning when others do not anymore, and the term "brain death" has been used to refer to various combinations. For example, although one major medical dictionary considers "brain death" to be synonymous with "cerebral death" (death of the cerebrum), the US National Library of Medicine Medical Subject Headings (MeSH) system defines brain death as including the brainstem. The distinctions are medically significant because, for example, in someone with a dead cerebrum but a living brainstem, spontaneous breathing may continue unaided, whereas in whole-brain death (which includes brainstem death), only life support equipment would maintain ventilation. In certain countries, patients classified as brain-dead may legally have their organs surgically removed for organ donation. Medicolegal history Differences in operational definitions of death have obvious medicolegal implications (in medical jurisprudence and medical law). Traditionally, both the legal and medical communities determined death through the permanent end of certain bodily functions in clinical death, especially respiration and heartbeat. With the increasing ability of the medical community to resuscitate people with no respiration, heartbeat, or other external signs of life, the need for another definition of death occurred, raising questions of legal death. This gained greater urgency with the widespread use of life support equipment and the rising capabilities and demand for organ transplantation. Since the 1960s, laws governing the determination of death have been implemented in all countries that have active organ transplantation programs. The first European country to adopt brain death as a legal definition (or indicator) of death was Finland in 1971, while in the United States, the state of Kansas had enacted a similar law earlier.An ad hoc committee at Harvard Medical School published a pivotal 1968 report to define irreversible coma. The Harvard criteria gradually gained consensus toward what is now known as brain death. In the wake of the 1976 Karen Ann Quinlan case, state legislatures in the United States moved to accept brain death as an acceptable indication of death. In 1981, a presidential commission issued a landmark report entitled Defining Death: Medical, Legal, and Ethical Issues in the Determination of Death, which rejected the "higher-brain" approach to death in favor of a "whole-brain" definition. This report formed the basis for the Uniform Determination of Death Act, since enacted in 39 states. Today, both the legal and medical communities in the US use "brain death" as a legal definition of death, allowing a person to be declared legally dead even if life support equipment maintains the bodys metabolic processes.In the UK, the Royal College of Physicians reported in 1995, abandoning the 1979 claim that the tests published in 1976 sufficed for the diagnosis of brain death, and suggesting a new definition of death based on the irreversible loss of brain-stem function alone. This new definition, the irreversible loss of the capacity for consciousness and for spontaneous breathing, and the essentially unchanged 1976 tests held to establish that state, have been adopted as a basis of death certification for organ transplant purposes in subsequent Codes of Practice. The Australia and New Zealand Intensive Care Society (ANZICS) states that the "determination of brain death requires that there is unresponsive coma, the absence of brain-stem reflexes and the absence of respiratory centre function, in the clinical setting in which these findings are irreversible. In particular, there must be definite clinical or neuro-imaging evidence of acute brain pathology (e.g. traumatic brain injury, intracranial haemorrhage, hypoxic encephalopathy) consistent with the irreversible loss of neurological function." In Brazil, the Federal Council of Medicine revised its regulations in 2017, including "a requirement for the patient to meet specific physiological prerequisites and for the physician to provide optimized care to the patient before starting the procedures for diagnosing brain death and to perform complementary tests, as well as the need for specific training for physicians who make this diagnosis." In 2020, an international panel of experts, the World Brain Death Project, published a guideline that:provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria (BD/DNC) in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries. Medical criteria Natural movements also known as the Lazarus sign or Lazarus reflex can occur on a brain-dead person whose organs have been kept functioning by life support. The living cells that can cause these movements are not living cells from the brain or brain stem; these cells come from the spinal cord. Sometimes these body movements can cause false hope for family members. A brain-dead individual has no clinical evidence of brain function upon physical examination. This includes no response to pain and no cranial nerve reflexes. Reflexes include pupillary response (fixed pupils), oculocephalic reflex, corneal reflex, no response to the caloric reflex test, and no spontaneous respirations. Brain death can sometimes be difficult to differentiate from other medical states such as barbiturate overdose, acute alcohol poisoning, sedative overdose, hypothermia, hypoglycemia, coma, and chronic vegetative states. Some comatose patients can recover to pre-coma or near pre-coma level of functioning, and some patients with severe irreversible neurological dysfunction will nonetheless retain some lower brain functions, such as spontaneous respiration, despite the losses of both cortex and brain stem functionality. Such is the case with anencephaly. Brain electrical activity can stop completely, or drop to such a low level as to be undetectable with most equipment. An EEG will therefore be flat, though this is sometimes also observed during deep anesthesia or cardiac arrest. Although in the United States a flat EEG test is not required to certify death, it is considered to have confirmatory value. In the UK it is not considered to be of value because any continuing activity it might reveal in parts of the brain above the brain stem is held to be irrelevant to the diagnosis of death on the Code of Practice criteria.The diagnosis of brain death is often required to be highly rigorous, in order to be certain that the condition is irreversible. Legal criteria vary, but in general require neurological examinations by two independent physicians. The exams must show complete and irreversible absence of brain function (brain stem function in UK), and may include two isoelectric (flat-line) EEGs 24 hours apart (less in other countries where it is accepted that if the cause of the dysfunction is a clear physical trauma there is no need to wait that long to establish irreversibility). The patient should have a normal temperature and be free of drugs that can suppress brain activity if the diagnosis is to be made on EEG criteria. Also, a radionuclide cerebral blood flow scan that shows complete absence of intracranial blood flow must be considered with other exams – temporary swelling of the brain, particularly within the first 72 hours, can lead to a false positive test on a patient that may recover with more time.CT angiography is neither required nor sufficient test to make the diagnosis.Confirmatory testing is only needed under the age of 1. For children and adults, testing is optional. Other situations possibly requiring confirmatory testing include severe facial trauma where determination of brainstem reflexes will be difficult, pre-existing pupillary abnormalities, and patients with severe sleep apnea and/or pulmonary disease. Confirmatory tests include: cerebral angiography, electroencephalography, transcranial Doppler ultrasonography, and cerebral scintigraphy (technetium Tc 99m exametazime). Cerebral angiography is considered the most sensitive confirmatory test in the determination of brain death. Organ donation While the diagnosis of brain death has become accepted as a basis for the certification of death for legal purposes, it is a very different state from biological death – the state universally recognized and understood as death. The continuing function of vital organs in the bodies of those diagnosed brain dead, if mechanical ventilation and other life-support measures are continued, provides optimal opportunities for their transplantation. When mechanical ventilation is used to support the body of a brain dead organ donor pending a transplant into an organ recipient, the donors date of death is listed as the date that brain death was diagnosed.In some countries (for instance, Spain, Finland, Wales, Portugal, and France), everyone is automatically an organ donor after diagnosis of death on legally accepted criteria, although some jurisdictions (such as Singapore, Spain, Wales, France, Czech Republic, Poland and Portugal) allow opting out of the system. Elsewhere, consent from family members or next-of-kin may be required for organ donation. In New Zealand, Australia, the United Kingdom (excluding Wales) and most states in the United States, drivers are asked upon application if they wish to be registered as an organ donor.In the United States, if the patient is at or near death, the hospital must notify a designated Organ Procurement Organization (OPO) of the details, and maintain the patient while the patient is being evaluated for suitability as a donor. The OPO searches to see if the deceased is registered as a donor, which serves as legal consent; if the deceased has not registered or otherwise noted consent (e.g., on a drivers license), the OPO will ask the next of kin for authorization. The patient is kept on ventilator support until the organs have been surgically removed. If the patient has indicated in an advance health care directive that they do not wish to receive mechanical ventilation or has specified a do-not-resuscitate(DNR) order and the patient has also indicated that they wish to donate their organs, some vital organs such as the heart and lungs may not be able to be recovered. Demographics United States Brain death is responsible for 2% of all adult and 5% of pediatric in-hospital deaths in the United States. In a nationwide survey of pediatric intensive care units (PICU) in the United States in 2019; there were more than 3,000 pediatric brain deaths out of a total of more than 15,344 children who died in PICUs. According to a national study, "brain death evaluations are performed infrequently, even in large PICUs." See also Eamonn Walker References == External links ==

Bullous pemphigoid

Bullous pemphigoid (type of pemphigoid) is an autoimmune pruritic skin disease which typically occurs in people aged over 60, that may involve the formation of blisters (bullae) in the space between the epidermal and dermal skin layers. It is classified as a type II hypersensitivity reaction, which involves formation of anti-hemidesmosome antibodies, causing a loss of keratinocytes to basement membrane adhesion. Signs and symptoms Clinically, the earliest lesions may appear as a hives-like red raised rash, but could also appear dermatitic, targetoid, lichenoid, nodular, or even without a rash (essential pruritus). Tense bullae eventually erupt, most commonly at the inner thighs and upper arms, but the trunk and extremities are frequently both involved. Any part of the skin surface can be involved. Oral lesions are present in a minority of cases. The disease may be acute, but can last from months to years with periods of exacerbation and remission. Several other skin diseases may have similar symptoms. However, milia are more common with epidermolysis bullosa acquisita, because of the deeper antigenic targets. A more ring-like configuration with a central depression or centrally collapsed bullae may indicate linear IgA disease. Nikolskys sign is negative, unlike pemphigus vulgaris, where it is positive. Causes In most cases of bullous pemphigoid, no clear precipitating factors are identified. Potential precipitating events that have been reported include exposure to ultraviolet light and radiation therapy. Onset of pemphigoid has also been associated with certain drugs, including furosemide, nonsteroidal anti-inflammatory agents, DPP-4 inhibitors, captopril, penicillamine, and antibiotics. Pathophysiology The bullae are formed by an immune reaction, initiated by the formation of IgG autoantibodies targeting dystonin, also called bullous pemphigoid antigen 1, and/or type XVII collagen, also called bullous pemphigoid antigen 2, which is a component of hemidesmosomes. A different form of dystonin is associated with neuropathy. Following antibody targeting, a cascade of immunomodulators results in a variable surge of immune cells, including neutrophils, lymphocytes and eosinophils coming to the affected area. Unclear events subsequently result in a separation along the dermoepidermal junction and eventually stretch bullae. Diagnosis Diagnosis consist of at least 2 positive results out of 3 criteria (2-out-of-3 rule): (1) pruritus and/or predominant cutaneous blisters, (2) linear IgG and/or C3c deposits (in an n- serrated pattern) by direct immunofluorescence microscopy (DIF) on a skin biopsy specimen, and (3) positive epidermal side staining by indirect immunofluorescence microscopy on human salt-split skin (IIF SSS) on a serum sample. Routine H&E staining or ELISA tests do not add value to initial diagnosis. Treatment Treatments include topical steroids such as clobetasol, and halobetasol which in some studies have proven to be equally effective as systemic, or pill, therapy and somewhat safer. However, in difficult-to-manage or widespread cases, systemic prednisone and powerful steroid-free immunosuppressant medications, such as methotrexate, azathioprine or mycophenolate mofetil, may be appropriate. Some of these medications have the potential for severe adverse effects such as kidney and liver damage, increased susceptibility to infections, and bone marrow suppression. Antibiotics such as tetracycline or erythromycin may also control the disease, particularly in patients who cannot use corticosteroids. The anti-CD20 monoclonal antibody rituximab has been found to be effective in treating some otherwise refractory cases of pemphigoid. A 2010 meta-analysis of 10 randomized controlled trials showed that oral steroids and potent topical steroids are effective treatments, although their use may be limited by side-effects, while lower doses of topical steroids are safe and effective for treatment of moderate bullous pemphigoid.IgA-mediated pemphigoid can often be difficult to treat even with usually effective medications such as rituximab. Prognosis Bullous pemphigoid may be self-resolving in a period ranging from several months to many years even without treatment. Poor general health related to old age is associated with a poorer prognosis. Epidemiology Very rarely seen in children, bullous and non-bullous pemphigoid most commonly occurs in people 70 years of age and older. Its estimated frequency is seven to 14 cases per million per year, but has been reported to be as high as 472 cases per million per year in Scottish men older than 85. At least one study indicates the incidence might be increasing in the United Kingdom. Some sources report it affects men twice as frequently as women, while others report no difference between the sexes.Many mammals can be affected, including dogs, cats, pigs, and horses, as well as humans. It is very rare in dogs; on average, three cases are diagnosed around the world each year. Research Animal models of bullous pemphigoid have been developed using transgenic techniques to produce mice lacking the genes for the two known autoantigens, dystonin and collagen XVII. See also Cicatricial pemphigoid Dystonin Gestational pemphigoid List of target antigens in pemphigoid List of immunofluorescence findings for autoimmune bullous conditions References Further reading == External links ==

Sleepwalking

Sleepwalking, also known as somnambulism or noctambulism, is a phenomenon of combined sleep and wakefulness. It is classified as a sleep disorder belonging to the parasomnia family. It occurs during slow wave stage of sleep, in a state of low consciousness, with performance of activities that are usually performed during a state of full consciousness. These activities can be as benign as talking, sitting up in bed, walking to a bathroom, consuming food, and cleaning, or as hazardous as cooking, driving a motor vehicle, violent gestures and grabbing at hallucinated objects.Although sleepwalking cases generally consist of simple, repeated behaviors, there are occasionally reports of people performing complex behaviors while asleep, although their legitimacy is often disputed. Sleepwalkers often have little or no memory of the incident, as their consciousness has altered into a state in which memories are difficult to recall. Although their eyes are open, their expression is dim and glazed over. This may last from 30 seconds to 30 minutes.Sleepwalking occurs during slow-wave sleep (N3) of non-rapid eye movement sleep (NREM sleep) cycles. It typically occurs within the first third of the night when slow-wave sleep is most prominent. Usually, it will occur once in a night, if at all. Signs and symptoms Sleepwalking is characterized by: partial arousal during non-rapid eye movement (NREM) sleep, typically during the first third of the night dream content that may or may not be recalled when awake dream-congruent motor behavior that may be simple or complex impaired perception of the environment impaired judgement, planning and problem-solving.Despite how it is portrayed in many cultures (eyes closed and walking with arms outstretched), the sleepwalkers eyes are open but may appear as a glassy-eyed stare or blank expression and pupils are dilated. They are often disoriented, consequent to awakening: the sleepwalker may be confused and perplexed, and might not know why or how they got out of bed; however, the disorientation will fade within minutes. They may talk while sleepwalking, but the talk typically does not make sense to the observer. There are varying degrees of amnesia associated with sleepwalking, ranging from no memory at all, vague memories or a narrative. Associated disorders In the study "Sleepwalking and Sleep Terrors in Prepubertal Children" it was found that, if a child had another sleep disorder – such as restless leg syndrome (RLS) or sleep-disorder breathing (SDB) – there was a greater chance of sleepwalking. The study found that children with chronic parasomnias may often also present SDB or, to a lesser extent, RLS. Furthermore, the disappearance of the parasomnias after the treatment of the SDB or RLS periodic limb movement syndrome suggests that the latter may trigger the former. The high frequency of SDB in family members of children with parasomnia provided additional evidence that SDB may manifest as parasomnias in children. Children with parasomnias are not systematically monitored during sleep, although past studies have suggested that patients with sleep terrors or sleepwalking have an elevated level of brief EEG arousals. When children receive polysomnographies, discrete patterns (e.g., nasal flow limitation, abnormal respiratory effort, bursts of high or slow EEG frequencies) should be sought; apneas are rarely found in children. Childrens respiration during sleep should be monitored with nasal cannula or pressure transducer system or esophageal manometry, which are more sensitive than the thermistors or thermocouples currently used in many laboratories. The clear, prompt improvement of severe parasomnia in children who are treated for SDB, as defined here, provides important evidence that subtle SDB can have substantial health-related significance. Also noteworthy is the report of familial presence of parasomnia. Studies of twin cohorts and families with sleep terror and sleepwalking suggest genetic involvement of parasomnias. RLS and SDB have been shown to have familial recurrence. RLS has been shown to have genetic involvement. Sleepwalking may also accompany the related phenomenon of night terrors, especially in children. In the midst of a night terror, the affected person may wander in a distressed state while still asleep, and examples of sufferers attempting to run or aggressively defend themselves during these incidents have been reported in medical literature.In some cases, sleepwalking in adults may be a symptom of a psychological disorder. One study suggests higher levels of dissociation in adult sleepwalkers, since test subjects scored unusually high on the hysteria portion of the "Crown-Crisp Experiential Index". Another suggested that "A higher incidence [of sleepwalking events] has been reported in patients with schizophrenia, hysteria and anxiety neuroses". Also, patients with migraine headaches or Tourette syndrome are 4–6 times more likely to sleepwalk. Consequences Most sleepwalkers get injuries at some point during sleepwalking, often minor injuries such as cuts or bruises. In rare occasions, however, sleepwalkers have fractured bones and died as the result of a fall. Sleepwalkers may also face embarrassment of being found naked in public. Causes The cause of sleepwalking is unknown. A number of, as yet unproven, hypotheses are suggested for why it might occur, including: delay in the maturity of the central nervous system, increased slow wave sleep, sleep deprivation, fever, and excessive tiredness. There may be a genetic component to sleepwalking. One study found that sleepwalking occurred in 45% of children who have one parent who sleepwalked, and in 60% of children if both parents sleepwalked. Thus, heritable factors may predispose an individual to sleepwalking, but expression of the behavior may also be influenced by environmental factors. Genetic studies using common fruit flies as experimental models reveal a link between night sleep and brain development mediated by evolutionary conserved transcription factors such as AP-2 Sleepwalking may be inherited as an autosomal dominant disorder with reduced penetrance. Genome-wide multipoint parametric linkage analysis for sleepwalking revealed a maximum logarithm of the odds score of 3.14 at chromosome 20q12-q13.12 between 55.6 and 61.4 cM.Sleepwalking has been hypothesized to be linked to the neurotransmitter serotonin, which also appears to be metabolized differently in migraine patients and people with Tourette syndrome, both populations being four to nine times more likely to experience an episode of sleepwalking. Hormonal fluctuations have been found to contribute to sleepwalking episodes in women, with the likeliness to sleepwalk being higher before the onset of menstruation. It also appears that hormonal changes during pregnancy decrease the likelihood of engaging in sleepwalking Medications, primarily in four classes—benzodiazepine receptor agonists and other GABA modulators, antidepressants and other serotonergic agents, antipsychotics, and β-blockers— have been associated with sleepwalking. The best evidence of medications causing sleepwalking is for Zolpidem and sodium oxybate; all other reports are based on associations noted in case reports.A number of conditions, such as Parkinsons disease, are thought to trigger sleepwalking in people without a previous history of sleepwalking. Diagnosis Polysomnography is the only accurate assessment of a sleepwalking episode. Because this is costly and sleepwalking episodes are usually infrequent, other measures commonly used include self-, parent-, or partner-report. Three common diagnostic systems that are generally used for sleepwalking disorders are International Classification of Diseases (ICD-10), the International Classification of Sleep Disorders (ICSD-3), and the Diagnostic and Statistical Manual.The Diagnostic and Statistical Manual defines two subcategories of sleepwalking, although sleepwalking does not need to involve either behaviours: sleepwalking with sleep-related eating. sleepwalking with sleep-related sexual behavior (sexsomnia).Sleep eating involves consuming food while asleep. These sleep eating disorders are more often than not induced for stress related reasons. Another major cause of this sleep eating subtype of sleepwalking is sleep medication, such as Ambien for example (Mayo Clinic). There are a few others, but Ambien is a more widely used sleep aid. Because many sleep eaters prepare the food they consume, there are risks involving burns and such with ovens and other appliances. As expected, weight gain is also a common outcome of this disorder, because food that is frequently consumed contains high carbohydrates. As with sleepwalking, there are ways that sleep eating disorders can be maintained. There are some medications that calm the sleeper so they can get longer and better-quality rest, but activities such as yoga can also be introduced to reduce the stress and anxiety causing the action. Differential diagnoses Sleepwalking should not be confused with alcohol- or drug-induced blackouts, which can result in amnesia for events similar to sleepwalking. During an alcohol-induced blackout (drug-related amnesia), a person is able to actively engage and respond to their environment (e.g. having conversations or driving a vehicle), however the brain does not create memories for the events. Alcohol-induced blackouts can occur with blood alcohol levels higher than 0.06g/dl. A systematic review of the literature found that approximately 50% of drinkers have experienced memory loss during a drinking episode and have had associated negative consequences similar to sleepwalkers, including injury and death.Other differential diagnoses include Rapid eye movement sleep behavior disorder, confusional arousals, and night terrors. Assessment An assessment of sleepwalking via polysomnography poses the problem that sleepwalking is less likely to occur in the sleep laboratory, and if an episode occurs, it is usually less complex than what the patient experiences at home. Therefore, the diagnosis can often be made by assessment of sleep history, time-course and content of the sleep related behaviors. Sometimes, home videos can provide additional information and should be considered in the diagnostic process.Some features that should always be assessed include: Age of onset When the episode occurs during the sleep period How often these episodes occur (frequency) and how long they last (duration) Description of the episode, including behavior, emotions, and thoughts during and after the event How responsive the patient is to external stimuli during the episode How conscious or aware the patient is, when awakened from an episode If the episode is remembered afterwards The triggers or precipitating factors Sleep–wake pattern and sleep environment Daytime sleepiness Other sleep disorders that might be present Family history for NREM parasomnias and other sleep disorders Medical, psychiatric, and neurological history Medication and substance use historyThe assessment should rule out differential diagnoses. Treatment There have been no clinical trials to show that any psychological or pharmacological intervention is effective in preventing sleepwalking episodes. Despite this, a wide range of treatments have been used with sleepwalkers. Psychological interventions have included psychoanalysis, hypnosis, scheduled or anticipatory waking, assertion training, relaxation training, managing aggressive feelings, sleep hygiene, classical conditioning (including electric shock), and play therapy. Pharmacological treatments have included tricyclic antidepressants (imipramine), an anticholinergic (biperiden), antiepileptics (carbamazepine, valproate), an antipsychotic (quetiapine), benzodiazepines (clonazepam, diazepam, flurazepam and triazolam), melatonin, a selective serotonin reuptake inhibitor (paroxetine), a barbiturate (sodium amytal) and herbs.There is no evidence to show that waking sleepwalkers is harmful or not, though the sleepwalker is likely to be disoriented if awakened as sleepwalking occurs during the deepest stage of sleep.Unlike other sleep disorders, sleepwalking is not associated with daytime behavioral or emotional problems. This may be because the sleepwalkers sleep is not disturbed—unless they are woken, they are still in a sleep state while sleepwalking.Maintaining the safety of the sleepwalker and others and seeking treatment for other sleep problems is recommended. Reassurance is recommended if sleepwalking is not causing any problems. However, if it causes distress or there is risk of harm, hypnosis and scheduled waking are recommended as treatments. Safety planning For those whose sleepwalking episodes are hazardous, a door alarm may offer a measure of protection. There are various kinds of door alarms that can attach to a bedroom door and when the door is opened, the alarm sounds. The intention is that the sound will fully awaken the person and interrupt the sleepwalking episode, or if the sleepwalker lives with others, the sound will prompt them to check on the person. Sleepwalkers should aim to have their bedrooms on the ground floor of a home, apartment, dorm, hotel, etc. Sleepwalkers should not have easily accessible weapons (loaded guns, knives) in the bedroom or any room of the house for that matter. If there are weapons, they should be locked away with keys secluded from the sleepwalker.For partners of sleepwalkers who are violent or disturb their sleep, sleeping in another room may lead to better sleep quality and quantity. Epidemiology The lifetime prevalence of sleepwalking is estimated to be 4.6%–10.3%. A meta-analysis of 51 studies, that included more than 100,000 children and adults, found that sleepwalking is more common in children with an estimated 5%, compared with 1.5% of adults, sleepwalking at least once in the previous 12 months. The rate of sleepwalking has not been found to vary across ages during childhood. History Sleepwalking has attracted a sense of mystery, but was not seriously investigated and diagnosed until the 19th century. The German chemist and parapsychologist Baron Karl Ludwig von Reichenbach (1788–1869) made extensive studies of sleepwalkers and used his discoveries to formulate his theory of the Odic force.Sleepwalking was initially thought to be a dreamer acting out a dream. For example, in one study published by the Society for Science & the Public in 1954, this was the conclusion: "Repression of hostile feelings against the father caused the patients to react by acting out in a dream world with sleepwalking, the distorted fantasies they had about all authoritarian figures, such as fathers, officers and stern superiors." This same group published an article twelve years later with a new conclusion: "Sleepwalking, contrary to most belief, apparently has little to do with dreaming. In fact, it occurs when the sleeper is enjoying his most oblivious, deepest sleep—a stage in which dreams are not usually reported." More recent research has discovered that sleepwalking is actually a disorder of NREM (non-rapid eye movement) arousal. Acting out a dream is the basis for a REM (rapid eye movement) sleep disorder called REM Behavior Disorder (or REM Sleep Behavior Disorder). More accurate data about sleep is due to the invention of technologies, such as the electroencephalogram (EEG) by Hans Berger in 1924 and BEAM by Frank Duffy in the early 1980s.In 1907, Sigmund Freud spoke about sleepwalking to the Vienna Psychoanalytic Society (Nunberg and Federn). He believed that sleepwalking was connected to fulfilling sexual wishes and was surprised that a person could move without interrupting their dream. At that time, Freud suggested that the essence of this phenomenon was the desire to go to sleep in the same area as the individual had slept in childhood. Ten years later, he speculated about somnambulism in the article "A Metapsychological Supplement to the Theory of Dreams" (1916–17 [1915]). In this essay, he clarified and expanded his hypothetical ideas on dreams. He described the dream as a fragile equilibrium that is destabilized by the repressed unconscious impulses of the unconscious system, which does not obey the wishes of the ego. Certain preconscious daytime thoughts can be resistant and these can retain a part of their cathexis as well. Unconscious impulses and day residues can come together and result in a conflict. Freud then wondered about the outcome of this wishful impulse: an unconscious instinctual demand that becomes a dream wish in the preconscious. Freud stated that this unconscious impulse could be expressed as mobility during sleep. This would be what is observed in somnambulism, though what actually makes it possible remains unknown.As of 2002, sleepwalking has not been detected in non-human primates. It is unclear whether it simply hasnt been observed yet, or whether sleepwalking is a uniquely human phenomenon. Society and culture Opera Vincenzo Bellinis 1831 Italian opera semiseria, La sonnambula, the plot of which is centered on the question of the innocence of the betrothed and soon-to-be married Amina, who, upon having been discovered in the bedchamber of a stranger, and despite the assurances of that stranger that Amina was entirely innocent, has been rejected by her enraged fiancé, Elvino — who, then, decides to marry another. In fact, when stressed, Amina was susceptible to somnambulism; and had come to be in the strangers bedchamber by sleep-walking along a high parapet (in full view of the operas audience). Elvino, who later observes the (exhausted by all the fuss) Amina, sleep-walking across a very high, very unstable, and very rickety bridge at the local mill, realizes his mistake, abandons his plans of marriage to the other woman, and re-unites with Amina. Jenny Lind and James Braid In August 1847, the famous soprano Jenny Lind visited Manchester, and gave two performances as Amina. The outstanding difference between Lind and her contemporaries was that, "whilst the beauty of her voice was far greater than any other in living memory (thus, the Swedish Nightingale), what really set her apart was her outstanding ability to act"; and, moreover, in performing as Amina, rather than walking along a wide and well-protected walkway (as the others did), she routinely acrobatically balanced her way along narrow planks.While she was in Manchester—on the basis that, at the time, many characterized "hypnotism" as "artificial somnambulism", and that, from a rather different perspective, her stage performance could also be described as one of "artificial" (rather than spontaneous) somnambulism—her friends arranged for her to visit the local surgeon James Braid, who had discovered hypnotism in 1841: "Mr. Braid, surgeon, whose discoveries in hypnotism are well known, having invited the fair impersonator of a somnambulist to witness some of the abnormal feats of a real somnambulist, artificially thrown into that state, it was arranged that a private séance should take place [on Friday, 3 September 1847]." Manchester Guardian, 8 September 1847. Drama The sleepwalking scene (Act V Scene 1) from William Shakespeares tragic play Macbeth (1606) is one of the most famous scenes in all of literature. In Walley Chamberlain Oultons two act farce The Sleep-Walker; or, Which is the Lady (1812), "Somno", a histrionic failed-actor-turned-manservant relives his wished-for roles when sleepwalking. Literature In Bram Stokers novel Dracula, the character Lucy Westenra is described as a sleepwalker. It is while sleepwalking that Count Dracula lures and attacks her. Sleepwalking as a legal defense As sleepwalking behaviours occur without volition, sleepwalking can be used as a legal defense, as a form of legal automatism. An individual can be accused of non-insane or insane automatism. The first is used as a defense for temporary insanity or involuntary conduct, resulting in acquittal. The latter results in a "special verdict of not guilty by reason of insanity." This verdict of insanity can result in a court order to attend a mental institution.In the 1963 case Bratty v A-G for Northern Ireland, Lord Morris stated, "Each set of facts must require a careful examination of its own circumstances, but if by way of taking an illustration it were considered possible for a person to walk in his sleep and to commit a violent crime while genuinely unconscious, then such a person would not be criminally liable for that act." While the veracity of the cases are disputed, there have been acts of homicide where the prime suspect may have committed the act while sleepwalking. Alternative explanations to homicidal or violent sleepwalking include malingering, drug-induced amnesia, and other disorders in which sleep-related violence may occur, such as REM Sleep Behavior Disorder, fugue states, and episodic wandering. Historical cases 1846, Albert Tirrell used sleepwalking as a defense against charges of murdering Maria Bickford, a prostitute living in a Boston brothel. 1961, Sergeant Willis Boshears confessed to strangling a local woman named Jean Constable in the early hours on New Years Day 1961, but claimed that he was asleep and only woke to realize what he had done. He pled not guilty on the basis of being asleep at the time he committed the offence and was acquitted. In 1981, Steven Steinberg of Scottsdale, Arizona was accused of killing his wife and acquitted on the grounds of temporary insanity. 1991, R v Burgess: Burgess was accused of hitting his girlfriend on the head with a wine bottle and then a video tape recorder. He was found not guilty at Bristol Crown Court, by reason of insane automatism. 1992, R. v. Parks: Parks was accused of killing his mother-in-law and attempting to kill his father-in-law. He was acquitted by the Supreme Court of Canada. 1994, Pennsylvania v. Ricksgers: Ricksgers was accused of killing his wife. He was sentenced to life in prison without parole. 1999, Arizona v. Falater: Scott Falater, of Phoenix, Arizona, was accused of killing his wife. The court concluded that the murder was too complex to be committed while sleepwalking. Falater was convicted of first-degree murder and sentenced to life with no possibility of parole. 2001, California v. Reitz: Stephen Reitz killed his lover, Eva Weinfurtner. He told police he had no recollection of the attack but he had "flashbacks" of believing he was in a scuffle with a male intruder. His parents testified in court that he had been a sleepwalker from childhood. The court convicted Reitz of first-degree murder in 2004. In 2001, Antonio Nieto murdered his wife and mother-in-law and attempted to murder his daughter and son, before being disarmed. Nieto claimed to have been asleep during the attack and dreaming that he was defending himself against aggressive ostriches. However, his children stated that he had recognized them and had told his son to not turn on the lights because their mother (gravely injured already) was sleeping. In 2007, Nieto was sentenced to 10 years internment in a psychiatric hospital and ordered to pay 171,100 euros as compensation to the victims. Jules Lowe confessed to causing the death of his father Edward in 2004, but did not remember committing the act. Jules used automatism as his defense, and was found not guilty by reason of insanity and detained indefinitely in a secure hospital. He was released after ten months. Brian Thomas was accused of killing his wife in 2008 while dreaming that he was fighting off intruders. He was freed in 2009 by a judge, who found him not guilty of murder. See also Rapid eye movement sleep behavior disorder References Sources Walker, N., Crime and Insanity in England Volume One: The Historical Perspective, Edinburgh: Edinburgh University Press (1968) External links Media related to Sleepwalking at Wikimedia Commons

Polycystic kidney disease

Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well. PKD is caused by abnormal genes that produce a specific abnormal protein; this protein has an adverse effect on tubule development. PKD is a general term for two types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The abnormal gene exists in all cells in the body; as a result, cysts may occur in the liver, seminal vesicles, and pancreas. This genetic defect can also cause aortic root aneurysms, and aneurysms in the circle of Willis cerebral arteries, which if they rupture, can cause a subarachnoid hemorrhage. Diagnosis may be suspected from one, some, or all of the following: new onset flank pain or red urine; a positive family history; palpation of enlarged kidneys on physical exam; an incidental finding on abdominal sonogram; or an incidental finding of abnormal kidney function on routine lab work (BUN, serum creatinine, or eGFR). Definitive diagnosis is made by abdominal CT exam. Complications include hypertension due to the activation of the renin–angiotensin–aldosterone system (RAAS), frequent cyst infections, urinary bleeding, and declining renal function. Hypertension is treated with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Infections are treated with antibiotics. Declining renal function is treated with renal replacement therapy (RRT): dialysis and/or transplantation. Management from the time of the suspected or definitive diagnosis is by a board-certified nephrologist. Signs and symptoms Signs and symptoms include high blood pressure, headaches, abdominal pain, blood in the urine, and excessive urination. Other symptoms include pain in the back, and cyst formation (renal and other organs). Cause PKD is caused by abnormal genes which produce a specific abnormal protein which has an adverse effect on tubule development. PKD is a general term for two types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). Autosomal dominant Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the inherited cystic kidney diseases with an incidence of 1:500 live births. Studies show that 10% of end-stage kidney disease (ESKD) patients being treated with dialysis in Europe and the U.S. were initially diagnosed and treated for ADPKD.Genetic mutations in any of the three genes PKD1, PKD2, and PKD3 have similar phenotypical presentations. Gene PKD1 is located on chromosome 16 and codes for a protein involved in regulation of cell cycle and intracellular calcium transport in epithelial cells, and is responsible for 85% of the cases of ADPKD. Gene PKD2 is identified, using genetic linkage study, on chromosome 4. A group of voltage-linked cation channels, with inward selectivity for K>Na>>Ca and outward selectivity for Ca2+ ≈ Ba2+ > Na+ ≈ K+, are coded for by PKD2 on chromosome 4. PKD3 recently appeared in research papers as a postulated third gene. Fewer than 10% of cases of ADPKD appear in non-ADPKD families. Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring kidney parenchyma, and progressively compromise kidney function. Autosomal recessive Autosomal recessive polycystic kidney disease (ARPKD) (OMIM #263200) is the less common of the two types of PKD, with an incidence of 1:20,000 live births and is typically identified in the first few weeks after birth. Unfortunately, the kidneys are often underdeveloped resulting in a 30% death rate in newborns with ARPKD. PKHD1 is involved. Mechanism Both autosomal dominant and autosomal recessive polycystic kidney disease cyst formation are tied to abnormal cilia-mediated signaling. The polycystin-1 and polycystin-2 proteins appear to be involved in both autosomal dominant and recessive polycystic kidney disease due to defects in both proteins. Both proteins have communication with calcium channel proteins, and causes reduction in resting (intracellular) calcium and endoplasmic reticulum storage of calcium.The disease is characterized by a ‘second hit’ phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic ‘hit’, resulting in renal tubular cyst formation and disease progression.PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. In the kidney, primary cilia have been found to be present on most cells of the nephron, projecting from the apical surface of the renal epithelium into the tubule lumen. The cilia were believed to bend in the urine flow, leading to changes in signalling, however this has since been shown to be an experimental error (the bending of cilia was an artifact of focal plane compensation, and also the actual effect on micturition by severe hypertension and cardiac arrest) and that bending of cilia does not contribute to alterations in Ca flux. While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Wnt/β-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). Function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades which produce differentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity. Diagnosis Polycystic kidney disease can be ascertained via a CT scan of abdomen, as well as, an MRI and ultrasound of the same area. A physical exam/test can reveal enlarged liver, heart murmurs and elevated blood pressure Natural history Most cases progress to bilateral disease in adulthood. Treatment In 2018, Jynarque (Tolvaptan) was introduced as the first FDA-approved treatment for PKD. In a recent long-term study, patients using Tolvaptan had a 6.4% higher kidney function after 5 years compared to standard of care. In 2019, a team of researchers at UCSB found that a ketogenic diet might be able to halt, or even reverse progression in mice, and the results of a first human case series study are showing potential benefit. The results of a 3-month randomized, prospective dietary intervention clinical trial are pending. In addition, recent research indicates that mild to moderate calorie restriction or time-restricted feeding slow the progression of autosomal dominant polycystic kidney disease (ADPKD) in mice Patient communities have been combining both ketogenic diets and time-restricted feeding with a low-oxalate diet to prevent the formation of stones and early reports show an average of 17% increase in kidney function after approximately one year on a ketogenic, time-restricted dietary regimen. If and when the disease progresses enough in a given case, the nephrologist or other practitioner and the patient will have to decide what form of renal replacement therapy will be used to treat end-stage kidney disease (kidney failure, typically stage 4 or 5 of chronic kidney disease).That will either be some form of dialysis, which can be done at least two different ways at varying frequencies and durations (whether it is done at home or in the clinic depends on the method used and the patients stability and training) and eventually, if they are eligible because of the nature and severity of their condition and if a suitable match can be found, unilateral or bilateral kidney transplantation.A Cochrane Review study of autosomal dominant polycystic kidney disease made note of the fact that it is important at all times, while avoiding antibiotic resistance, to control infections of the cysts in the kidneys, and if affected, the liver, when needed for a certain duration to combat infection, by using, "bacteriostatic and bacteriocidal drugs". Prognosis ADPKD individuals might have a normal life; conversely, ARPKD can cause kidney dysfunction and can lead to kidney failure by the age of 40–60. ADPKD1 and ADPKD2 are very different, in that ADPKD2 is much milder.Currently, there are no therapies proven effective to prevent the progression of ADPKD. Epidemiology PKD is one of the most common hereditary diseases in the United States, affecting more than 600,000 people. It is the cause of nearly 10% of all end-stage renal disease. It equally affects men, women, and all races. PKD occurs in some animals as well as humans. See also Autosomal recessive polycystic kidney disease References Further reading == External links ==

Dysgeusia

Dysgeusia, also known as parageusia, is a distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is a decrease in taste sensitivity. An alteration in taste or smell may be a secondary process in various disease states, or it may be the primary symptom. The distortion in the sense of taste is the only symptom, and diagnosis is usually complicated since the sense of taste is tied together with other sensory systems. Common causes of dysgeusia include chemotherapy, asthma treatment with albuterol, and zinc deficiency. Liver disease, hypothyroidism, and rarely certain types of seizures can also lead to dysgeusia. Different drugs could also be responsible for altering taste and resulting in dysgeusia. Due to the variety of causes of dysgeusia, there are many possible treatments that are effective in alleviating or terminating the symptoms of dysgeusia. These include artificial saliva, pilocarpine, zinc supplementation, alterations in drug therapy, and alpha lipoic acid. Signs and symptoms The alterations in the sense of taste, usually a metallic taste, and sometimes smell are the only symptoms. Causes Chemotherapy A major cause of dysgeusia is chemotherapy for cancer. Chemotherapy often induces damage to the oral cavity, resulting in oral mucositis, oral infection, and salivary gland dysfunction. Oral mucositis consists of inflammation of the mouth, along with sores and ulcers in the tissues. Healthy individuals normally have a diverse range of microbial organisms residing in their oral cavities; however, chemotherapy can permit these typically non-pathogenic agents to cause serious infection, which may result in a decrease in saliva. In addition, patients who undergo radiation therapy also lose salivary tissues. Saliva is an important component of the taste mechanism. Saliva both interacts with and protects the taste receptors in the mouth. Saliva mediates sour and sweet tastes through bicarbonate ions and glutamate, respectively. The salt taste is induced when sodium chloride levels surpass the concentration in the saliva. It has been reported that 50% of chemotherapy patients have had either dysgeusia or another form of taste impairment. Examples of chemotherapy treatments that can lead to dysgeusia are cyclophosphamide, cisplatin, vismodegib, and etoposide. The exact mechanism of chemotherapy-induced dysgeusia is unknown. Taste buds Distortions in the taste buds may give rise to dysgeusia. In a study conducted by Masahide Yasuda and Hitoshi Tomita from Nihon University of Japan, it has been observed that patients with this taste disorder have fewer microvilli than normal. In addition, the nucleus and cytoplasm of the taste bud cells have been reduced. Based on their findings, dysgeusia results from loss of microvilli and the reduction of Type III intracellular vesicles, all of which could potentially interfere with the gustatory pathway. Radiation to head and neck also results in direct destruction of taste buds, apart from effects of altered salivary output. Zinc deficiency Another primary cause of dysgeusia is zinc deficiency. While the exact role of zinc in dysgeusia is unknown, it has been cited that zinc is partly responsible for the repair and production of taste buds. Zinc somehow directly or indirectly interacts with carbonic anhydrase VI, influencing the concentration of gustin, which is linked to the production of taste buds. It has also been reported that patients treated with zinc experience an elevation in calcium concentration in the saliva. In order to work properly, taste buds rely on calcium receptors. Zinc “is an important cofactor for alkaline phosphatase, the most abundant enzyme in taste bud membranes; it is also a component of a parotid salivary protein important to the development and maintenance of normal taste buds.” Drugs There are also a wide variety of drugs that can trigger dysgeusia, including zopiclone, H1-antihistamines, such as azelastine and emedastine. Approximately 250 drugs affect taste, including Paxlovid, a drug used to treat COVID-19. Some describe so-called "Paxlovid mouth" as like a "mouthful of dirty pennies and rotten soymilk," according to the Wall Street Journal.The sodium channels linked to taste receptors can be inhibited by amiloride, and the creation of new taste buds and saliva can be impeded by antiproliferative drugs. Saliva can have traces of the drug, giving rise to a metallic flavor in the mouth; examples include lithium carbonate and tetracyclines. Drugs containing sulfhydryl groups, including penicillamine and captopril, may react with zinc and cause deficiency. Metronidazole and chlorhexidine have been found to interact with metal ions that associate with the cell membrane. Drugs that act by blocking the renin - angiotensin - aldosterone system, for example by antagonizing the angiotensin II receptor (as eprosartan does), have been linked to dysgeusia. There are few case reports claiming calcium channel blockers like Amlodipine also cause dysguesia by blocking calcium sensitive taste buds. Pregnancy Changes in hormone levels during pregnancy, such as estrogen, can affect the sense of taste. A study found that 93 percent of pregnant women reported some change in taste during pregnancy. Miscellaneous causes Xerostomia, also known as dry mouth syndrome, can precipitate dysgeusia because normal salivary flow and concentration are necessary for taste. Injury to the glossopharyngeal nerve can result in dysgeusia. In addition, damage done to the pons, thalamus, and midbrain, all of which compose the gustatory pathway, can be potential factors. In a case study, 22% of patients who were experiencing a bladder obstruction were also experiencing dysgeusia. Dysgeusia was eliminated in 100% of these patients once the obstruction was removed. Although it is uncertain what the relationship between bladder relief and dysgeusia entails, it has been observed that the areas responsible for urinary system and taste in the pons and cerebral cortex in the brain are close in proximity.Dysgeusia often occurs for unknown reasons. A wide range of miscellaneous factors may contribute to this taste disorder, such as gastric reflux, lead poisoning, and diabetes mellitus. A minority of pine nuts can apparently cause taste disturbances, for reasons which are not entirely proven. Certain pesticides can have damaging effects on the taste buds and nerves in the mouth. These pesticides include organochloride compounds and carbamate pesticides. Damage to the peripheral nerves, along with injury to the chorda tympani branch of the facial nerve, also cause dysgeusia. A surgical risk for laryngoscopy and tonsillectomy include dysgeusia. Patients with the burning mouth syndrome, most likely menopausal women, often have dysgeusia as well. Normal function The sense of taste is based on the detection of chemicals by specialized taste cells in the mouth. The mouth, throat, larynx, and esophagus all have taste buds, which are replaced every ten days. Each taste bud contains receptor cells. Afferent nerves make contact with the receptor cells at the base of the taste bud. A single taste bud is innervated by several afferent nerves, while a single efferent fiber innervates several taste buds. Fungiform papillae are present on the anterior portion of the tongue while circumvallate papillae and foliate papillae are found on the posterior portion of the tongue. The salivary glands are responsible for keeping the taste buds moist with saliva.A single taste bud is composed of four types of cells, and each taste bud has between 30 and 80 cells. Type I cells are thinly shaped, usually in the periphery of other cells. They also contain high amounts of chromatin. Type II cells have prominent nuclei and nucleoli with much less chromatin than Type I cells. Type III cells have multiple mitochondria and large vesicles. Type I, II, and III cells also contain synapses. Type IV cells are normally rooted at the posterior end of the taste bud. Every cell in the taste bud forms microvilli at the ends. Diagnosis In general, gustatory disorders are challenging to diagnose and evaluate. Because gustatory functions are tied to the sense of smell, the somatosensory system, and the perception of pain (such as in tasting spicy foods), it is difficult to examine sensations mediated through an individual system. In addition, gustatory dysfunction is rare when compared to olfactory disorders.Diagnosis of dysgeusia begins with the patient being questioned about salivation, swallowing, chewing, oral pain, previous ear infections (possibly indicated by hearing or balance problems), oral hygiene, and stomach problems. The initial history assessment also considers the possibility of accompanying diseases such as diabetes mellitus, hypothyroidism, or cancer. A clinical examination is conducted and includes an inspection of the tongue and the oral cavity. Furthermore, the ear canal is inspected, as lesions of the chorda tympani have a predilection for this site. Gustatory testing In order to further classify the extent of dysgeusia and clinically measure the sense of taste, gustatory testing may be performed. Gustatory testing is performed either as a whole-mouth procedure or as a regional test. In both techniques, natural or electrical stimuli can be used. In regional testing, 20 to 50 µL of liquid stimulus is presented to the anterior and posterior tongue using a pipette, soaked filter-paper disks, or cotton swabs. In whole mouth testing, small quantities (2-10 mL) of solution are administered, and the patient is asked to swish the solution around in the mouth.Threshold tests for sucrose (sweet), citric acid (sour), sodium chloride (salty), and quinine or caffeine (bitter) are frequently performed with natural stimuli. One of the most frequently used techniques is the "three-drop test." In this test, three drops of liquid are presented to the subject. One of the drops is of the taste stimulus, and the other two drops are pure water. Threshold is defined as the concentration at which the patient identifies the taste correctly three times in a row.Suprathreshold tests, which provide intensities of taste stimuli above threshold levels, are used to assess the patients ability to differentiate between different intensities of taste and to estimate the magnitude of suprathreshold loss of taste. From these tests, ratings of pleasantness can be obtained using either the direct scaling or magnitude matching method and may be of value in the diagnosis of dysgeusia. Direct scaling tests show the ability to discriminate among different intensities of stimuli and whether a stimulus of one quality (sweet) is stronger or weaker than a stimulus of another quality (sour). Direct scaling cannot be used to determine if a taste stimulus is being perceived at abnormal levels. In this case, magnitude matching is used, in which a patient is asked to rate the intensities of taste stimuli and stimuli of another sensory system, such as the loudness of a tone, on a similar scale. For example, the Connecticut Chemosensory Clinical Research Center asks patients to rate the intensities of NaCl, sucrose, citric acid and quinine-HCl stimuli, and the loudness of 1000 Hz tones.Other tests include identification or discrimination of common taste substances. Topical anesthesia of the tongue has been reported to be of use in the diagnosis of dysgeusia as well, since it has been shown to relieve the symptoms of dysgeusia temporarily. In addition to techniques based on the administration of chemicals to the tongue, electrogustometry is frequently used. It is based on the induction of gustatory sensations by means of an anodal electrical direct current. Patients usually report sour or metallic sensations similar to those associated with touching both poles of a live battery to the tongue. Although electrogustometry is widely used, there seems to be a poor correlation between electrically and chemically induced sensations. Diagnostic tools Certain diagnostic tools can also be used to help determine the extent of dysgeusia. Electrophysiological tests and simple reflex tests may be applied to identify abnormalities in the nerve-to-brainstem pathways. For example, the blink reflex may be used to evaluate the integrity of the trigeminal nerve–pontine brainstem–facial nerve pathway, which may play a role in gustatory function.Structural imaging is routinely used to investigate lesions in the taste pathway. Magnetic resonance imaging allows direct visualization of the cranial nerves. Furthermore, it provides significant information about the type and cause of a lesion. Analysis of mucosal blood flow in the oral cavity in combination with the assessment of autonomous cardiovascular factors appears to be useful in the diagnosis of autonomic nervous system disorders in burning mouth syndrome and in patients with inborn disorders, both of which are associated with gustatory dysfunction. Cell cultures may also be used when fungal or bacterial infections are suspected.In addition, the analysis of saliva should be performed, as it constitutes the environment of taste receptors, including transport of tastes to the receptor and protection of the taste receptor. Typical clinical investigations involve sialometry and sialochemistry. Studies have shown that electron micrographs of taste receptors obtained from saliva samples indicate pathological changes in the taste buds of patients with dysgeusia and other gustatory disorders. Treatments Artificial saliva and pilocarpine Because medications have been linked to approximately 22% to 28% of all cases of dysgeusia, researching a treatment for this particular cause has been important. Xerostomia, or a decrease in saliva flow, can be a side effect of many drugs, which, in turn, can lead to the development of taste disturbances such as dysgeusia. Patients can lessen the effects of xerostomia with breath mints, sugarless gum, or lozenges, or physicians can increase saliva flow with artificial saliva or oral pilocarpine. Artificial saliva mimics the characteristics of natural saliva by lubricating and protecting the mouth but does not provide any digestive or enzymatic benefits. Pilocarpine is a cholinergic drug meaning it has the same effects as the neurotransmitter acetylcholine. Acetylcholine has the function of stimulating the salivary glands to actively produce saliva. The increase in saliva flow is effective in improving the movement of tastants to the taste buds. Zinc deficiency Zinc supplementation Approximately one half of drug-related taste distortions are caused by a zinc deficiency. Many medications are known to chelate, or bind, zinc, preventing the element from functioning properly. Due to the causal relationship of insufficient zinc levels to taste disorders, research has been conducted to test the efficacy of zinc supplementation as a possible treatment for dysgeusia. In a randomized clinical trial, fifty patients with idiopathic dysgeusia were given either zinc or a lactose placebo. The patients prescribed the zinc reported experiencing improved taste function and less severe symptoms compared to the control group, suggesting that zinc may be a beneficial treatment. The efficacy of zinc, however, has been ambiguous in the past. In a second study, 94% of patients who were provided with zinc supplementation did not experience any improvement in their condition. This ambiguity is most likely due to small sample sizes and the wide range of causes of dysgeusia. A recommended daily oral dose of 25–100 mg, as zinc gluconate, appears to be an effective treatment for taste dysfunction provided that there are low levels of zinc in the blood serum. There is not a sufficient amount of evidence to determine whether or not zinc supplementation is able to treat dysgeusia when low zinc concentrations are not detected in the blood.A Cochrane Review in 2017 assessed the effects of different interventions for the management of taste disturbances. There was very low-quality evidence to support the role of zinc supplementation in the improvement of taste acuity and taste discrimination in patients with zinc deficiency or idiopathic taste disorders. Further research is required to improve the quality of evidence for zinc supplementation as an effective intervention for the management of dysgeusia. Zinc infusion in chemotherapy It has been reported that approximately 68% of cancer patients undergoing chemotherapy experience disturbances in sensory perception such as dysgeusia. In a pilot study involving twelve lung cancer patients, chemotherapy drugs were infused with zinc in order to test its potential as a treatment. The results indicated that, after two weeks, no taste disturbances were reported by the patients who received the zinc-supplemented treatment while most of the patients in the control group who did not receive the zinc reported taste alterations. A multi-institutional study involving a larger sample size of 169 patients, however, indicated that zinc-infused chemotherapy did not have an effect on the development of taste disorders in cancer patients. An excess amount of zinc in the body can have negative effects on the immune system, and physicians must use caution when administering zinc to immunocompromised cancer patients. Because taste disorders can have detrimental effects on a patients quality of life, more research needs to be conducted concerning possible treatments such as zinc supplementation. Altering drug therapy The effects of drug-related dysgeusia can often be reversed by stopping the patients regimen of the taste altering medication. In one case, a forty-eight-year-old woman who had hypertension was being treated with valsartan. Due to this drugs inability to treat her condition, she began taking a regimen of eprosartan, an angiotensin II receptor antagonist. Within three weeks, she began experiencing a metallic taste and a burning sensation in her mouth that ceased when she stopped taking the medication. When she began taking eprosartan on a second occasion, her dysgeusia returned. In a second case, a fifty-nine-year-old man was prescribed amlodipine in order to treat his hypertension. After eight years of taking the drug, he developed a loss of taste sensation and numbness in his tongue. When he ran out of his medication, he decided not to obtain a refill and stopped taking amlodipine. Following this self-removal, he reported experiencing a return of his taste sensation. Once he refilled his prescription and began taking amlodipine a second time, his taste disturbance reoccurred. These two cases suggest that there is an association between these drugs and taste disorders. This link is supported by the "de-challenge" and "re-challenge" that took place in both instances. It appears that drug-induced dysgeusia can be alleviated by reducing the drugs dose or by substituting a second drug from the same class. Alpha lipoic acid Alpha lipoic acid (ALA) is an antioxidant that is made naturally by human cells. It can also be administered in capsules or can be found in foods such as red meat, organ meats, and yeast. Like other antioxidants, it functions by ridding the body of harmful free radicals that can cause damage to tissues and organs. It has an important role in the Krebs cycle as a coenzyme leading to the production of antioxidants, intracellular glutathione, and nerve-growth factors. Animal research has also uncovered the ability of ALA to improve nerve conduction velocity. Because flavors are perceived by differences in electric potential through specific nerves innervating the tongue, idiopathic dysgeusia may be a form of a neuropathy. ALA has proven to be an effective treatment for burning mouth syndrome spurring studies in its potential to treat dysgeusia. In a study of forty-four patients diagnosed with the disorder, one half was treated with the drug for two months while the other half, the control group, was given a placebo for two months followed by a two-month treatment of ALA. The results reported show that 91% of the group initially treated with ALA reported an improvement in their condition compared to only 36% of the control group. After the control group was treated with ALA, 72% reported an improvement. This study suggests that ALA may be a potential treatment for patients and supports that full double blind randomized studies should be performed. Managing dysgeusia In addition to the aforementioned treatments, there are also many management approaches that can alleviate the symptoms of dysgeusia. These include using non-metallic silverware, avoiding metallic or bitter tasting foods, increasing the consumption of foods high in protein, flavoring foods with spices and seasonings, serving foods cold in order to reduce any unpleasant taste or odor, frequently brushing ones teeth and utilizing mouthwash, or using sialogogues such as chewing sugar-free gum or sour-tasting drops that stimulate the productivity of saliva. When taste is impeded, the food experience can be improved through means other than taste, such as texture, aroma, temperature, and color. Psychological impacts People with dysgeusia are also forced to manage the impact that the disorder has on their quality of life. An altered taste has effects on food choice and intake and can lead to weight loss, malnutrition, impaired immunity, and a decline in health. Patients diagnosed with dysgeusia must use caution when adding sugar and salt to food and must be sure not to overcompensate for their lack of taste with excess amounts. Since the elderly are often on multiple medications, they are at risk for taste disturbances increasing the chances of developing depression, loss of appetite, and extreme weight loss. This is cause for an evaluation and management of their dysgeusia. In patients undergoing chemotherapy, taste distortions can often be severe and make compliance with cancer treatment difficult. Other problems that may arise include anorexia and behavioral changes that can be misinterpreted as psychiatric delusions regarding food. Symptoms including paranoia, amnesia, cerebellar malfunction, and lethargy can also manifest when undergoing histidine treatment. Future research Every year, more than 200,000 individuals see their physicians concerning chemosensory problems, and many more taste disturbances are never reported. Due to the large number of persons affected by taste disorders, basic and clinical research are receiving support at different institutions and chemosensory research centers across the country. These taste and smell clinics are focusing their research on better understanding the mechanisms involved in gustatory function and taste disorders such as dysgeusia. For example, the National Institute on Deafness and Other Communication Disorders is looking into the mechanisms underlying the key receptors on taste cells and applying this knowledge to the future of medications and artificial food products. Meanwhile, the Taste and Smell Clinic at the University of Connecticut Health Center is integrating behavioral, neurophysiological, and genetic studies involving stimulus concentrations and intensities in order to better understand taste function. See also Anosmia Parosmia References External links Dysgeusia at NIH

Chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.CMML shows characteristics of a myelodysplastic syndrome (MDS); a disorder that produces abnormal looking blood cells, and a myeloproliferative neoplasm (MPN); a disorder characterised by the overproduction of blood cells. For this reason, CMML was reclassified as a MDS/MPN overlap disorder in 2002. For a diagnosis of CMML, the World Health Organization (WHO) states that the blood monocyte count must be >1x109/L, no Philadelphia chromosome or mutations in the PDGFRA or PDGFRB gene should be present, the blast count must be <20% and dysplasia of at least one lineage of myeloid blood cell should be present.Azacitidine is a drug used to treat CMML and is approved by the Food and Drug Administration (FDA) and the European Medicines Agency. Stem cell transplant is also used to treat CMML, and involves the transplantation of donor haematopoietic stem cells into the recipient. Blood transfusion and erythropoietin are used to treat disease associated anaemia. Signs and symptoms One of the most common signs of CMML is splenomegaly, found in approximately half of cases. Other less frequent signs and symptoms consist of anaemia, fever, weight loss, night sweats, infection, bleeding, synovitis, lymphadenopathy, skin rashes, pleural effusion, pericardial effusion and peritoneal effusion. Cause Although the cause of CMML is unknown, environmental carcinogens, ionising radiation and cytotoxic agents may have a role in causing disease. Approximately one third of cases of MDS with a monocyte count of >10% and <1x109/L will progress to CMML. Pathogenesis With a high rate of Ras mutation in CMML, deregulation of this signalling pathway has been linked to the pathogenesis of the disease. Tumour necrosis factor, GM-CSF, interleukin-3, interleukin-4, interleukin-6, and interleukin-10 may have a role in hyperproliferative CMML cells. These cytokines can stimulate the growth of CMML in vitro. Hypermethylation of cytosine residues (usually in the promoter regions of genes) occurs in many malignancies to regulate gene expression. One commonly hypermethylated gene in CMML is p15INK4b, a gene involved in cell cycle regulation. Genetic mutations Clonal genetic abnormalities are common in CMML but they are not specific for diagnosis of the disease. The most common found are the 8+, −7/del (7q) and structural 12p abnormalities. KRAS and NRAS are mutated in 25–40% of the cases of CMML. The Jak2 V617F mutation is found in 10% of cases. Mutations in transcription factors such as RUNX1, CEBPA, NPM1 and WT1 have been found in up to 30% of cases. Mutations of CBL are found in approximately 5–18% of cases. Mutations in the TET2 gene are found in approximately 40–50% of CMML. Inactivating mutations in one of the two parental GATA2 genes lead to a reduction, i.e. a haploinsufficiency, in the cellular levels of the genes product, the GATA2 transcription factor, and thereby to a rare autosomal dominant genetic disease, GATA2 deficiency. This disease is associated with a highly variable set of disorders including the myelodysplastic syndrome, acute myeloid leukemia, and CMML. GATA2-deficiency-induced CMML, like other types of CMML, is commonly preceded by monocytosis. Diagnosis Blood films display a range of abnormalities. A monocyte count of >1x109/L is essential for a diagnosis of CMML. Other features may include; leukocytosis (50% of cases); left shift and dysplasia of monocytes and granulocytes; presence of metamyelocytes, myelocytes and promonocytes; monocytes with hypersegmented/abnormal shaped nuclei, increased cytoplasmic basophilia and/or the presence of cytoplasmic granules; eosinophilia (in cases of CMML with eosinophilia); and spherocytosis (in cases of direct Coombs test, DCT, positive haemolytic anaemia). Platelet counts may be reduced, increased or normal. Haemoglobin levels are usually reduced with normocytic and normochromic red blood cells. Autoantibodies and cold agglutinins may be present and 10% of CMML is DCT positive.Bone marrow aspirates will display hypercellularity with increased counts of granulocytic and monocytic cells. Bone marrow core biopsies may show a predominance of myelocytic and monocytic cells, abnormal localisation of immature precursors and dysplastic megakaryocytes. Monocytic nodules are a common feature in biopsies.The phenotypical characteristics of CMML are; CD11b, CD11c, CD14, CD33, CD45 and CD64 seen in 100% of cases; CD13 found in 95% of cases; CD4 found in 76% of cases; HLA-DR found in 71% of cases; CD56 found in 53% of cases; CD2 found in 34% of cases; CD16 found in 29% of cases; CD10 found in 28% of cases; CD23 and CD7 found in 9% of cases; and CD117 found in 5% of cases. Classification Leukemia subtypes are categorised into single clinical entities so that they can be diagnosed and treated appropriately. Leukaemias are subdivided into lymphoid and myeloid neoplasms, depending on which bone marrow cells are cancerous. The myeloid neoplasms contain acute and chronic leukemias, myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MPNs are characterised by increased production of myeloid blood cells, with a higher than normal number of mature cells. Unlike MPNs, MDSs have a dysfunctional production of myeloid cells with a reduced number of mature cells. Many of the cells produced in MDS are abnormal looking, known as dysplasia. CMML shows characteristics of both groups and thus is a difficult disease to categorise. FAB classification The French-American-British (FAB) classification system was published in 1976 to classify the leukaemias. It placed CMML into the category of MDS, along with the refractory anaemia, refractory anaemia with ring sideroblasts, refractory anaemia with excess blasts and refractory anaemia with excess blasts in transformation. The system does have clinical utility; however factors such as cytogenetic status are not within the remit of the classification. For this reason, many disease entities in these groups show a great deal of heterogeneity. WHO classification In 2001, the WHO Classification of Myeloid Neoplasms was published, classifying CMML into a new group of diseases, the myelodysplastic/myeloproliferative neoplasms (MDS/MPN), reflecting the diseases neoplastic nature. Other diseases in this category are juvenile myelomonocytic leukaemia, atypical CML; BCR-ABL1 negative and MDS/MPD unclassifiable. These MDS/MPN overlap syndromes have effective production of some lineages of blood cells, but show ineffective proliferation of other lineages. The 2008 revision of the classification moved cases of CMML with PDGFR gene translocations to a new group, myeloid/lymphoid neoplasms with eosinophilia with abnormalities of PDGFRA, PDGFRB or FGFR1. Diagnostic criteria FAB criteria The FAB criteria for diagnosis are as follows: Monocyte count >1x109/L 0–19% blasts in bone marrow <5% blasts in peripheral bloodThe FAB also arbitrarily categorises CMML into myelodysplastic-like and myeloproliferative-like groups. A white blood count of 13x109 is used as a cut-off to differentiate the two. WHO criteria The WHO criteria for diagnosis are as follows: Persistent peripheral blood monocytosis with counts >1x109/L No Philadelphia chromosome or BCR-ABL1 fusion gene No rearrangement of PDGFRA or PDGFRB gene <20% myeloblasts, monoblasts and promonocytes in peripheral blood or bone marrow Dysplasia in one or more of the myeloid lineages; if myelodysplasia is absent or minimal then a diagnosis of CMML can be made if other requirements are met and: A molecular genetic abnormality is present in haematopoietic cells, or Monocytosis present for ≥3 months and other causes of monocytosis have been ruled outWHO defined CMML has two main subsets, CMML-1 and CMML-2. CMML-1 is diagnosed if myeloblasts, monoblasts and promonocytes are <5% of peripheral blood and <10% of bone marrow. CMML-2 is diagnosed if: Myeloblasts, monoblasts or promonocytes are 5-19% in blood, or Myeloblasts, monoblasts or promonocytes are 10-19% in bone marrow, or Auer rods are presentCMML-1 and CMML-2 can be additionally grouped as CMML-1 or CMML-2 with eosinophilia. These are diagnosed if the above criteria are met and the blood eosinophil count is >1.5x109/L.Presence of two or more phenotypic abnormalities can aid a diagnosis of CMML in the absence of identifying cytogenetic or dysplastic features. These can include the expression of CD56 and/or CD2, or under-expression of HLA-DR. Prognosis Factors affecting prognosis CMML-2 has a reduced overall survival as compared with CMML-1, with median survivals of 15 and 20 months, respectively. Myeloproliferative CMML (>13x109 monocytes/L) has a reduced survival compared with myelodysplastic CMML. A platelet count of <100 x109/L reduces overall survival. A haemoglobin level of <10g/dL has a reduced overall survival. Some cytogenetic abnormalities have implications on the prognosis of CMML. Normal karyotypes or the single loss of the Y chromosome have low risk prognoses. Trisomy 8, chromosome 7 abnormalities and complex karyotypes comprise a high risk group. Other cytogenetic abnormalities have intermediate prognoses. Somatic mutations in genes such as ASXL1 and EZH2 are associated with a poor prognosis.CMML has a 20–30% chance of transformation to AML, a lower rate than other similar diseases. The CMML-2 subtype is associated with increased risk of transformation and ASXL1 and RUNX1 mutations also increase the risk of transition to AML. Scoring systems IPSS The International Prognostic Scoring System (IPSS) was developed in the mid-1990s to assess the prognosis of MDS patients. This system stratifies cases into 2 groups; a lower-risk group (sub divided into low and intermediate-1) and a higher risk (subdivided into intermediate-2 and high). It uses the blast percentage, number of cytopenias and bone marrow cytogenetics data to place cases of CMML into these groups. Due to the scoring system being developed for MDS, the more myeloproliferative cases of CMML (WBC >13x109) are excluded from the scoring system. Although the IPSS scoring system is used clinically, there is a high variability in each group. For this reason, new modalities for assessing prognosis in MDS (and CMML) are being developed. MD Anderson Prognostic Scoring System A new method developed using data from the M.D. Anderson Cancer Center found that a haemoglobin level of <12g/dL, total circulating lymphocyte count of >2.5 x 109/L, >0% immature myeloid cells, >10% bone marrow blasts causes a reduced overall survival. This data allows cases of CMML to be stratified into low, intermediate-1, intermediate-2 and high risk groups. These groups have median survival times of 24, 15, 8 and 5 months respectively. The Düsseldorf score The Düsseldorf score stratifies cases using four categories, giving one point for each; bone marrow blasts ≥5%, LDH >200U/L, haemoglobin ≤9g/dL and a platelet count ≤100,000/uL. A score of 0 indicates a low risk group 1-2 indicates an intermediate risk group and 3-4 indicates a high risk group. The cumulative 2 year survival of scores 0, 1-2 and 3-4 is 91%, 52% and 9%; and risk of AML transformation is 0%, 19% and 54% respectively. Treatment The treatment of CMML remains challenging due to the lack of clinical trials investigating the disease as its own clinical entity. It is often grouped with MDS in clinical trials, and for this reason the treatment of CMML is very similar to that of MDS. Most cases are dealt with as supportive rather than curative because most therapies do not effectively increase survival. Indications for treatment include the presence of B symptoms, symptomatic organ involvement, increasing blood counts, hyperleukocytosis, leukostasis and/or worsening cytopenias.Blood transfusions and erythropoietin administration are used to raise haemoglobin levels in cases with anemia.Azacitidine is a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of CMML and by the European Medicines Agency (EMA) for high risk non-proliferative CMML with 10–19% marrow blasts. It is a cytidine analogue that causes hypomethylation of DNA by inhibition of DNA methyltransferase. Decitabine is a similar drug to azacitidine and is approved by the FDA for treatments of all subtypes of MDS, including CMML. Hydroxyurea is a chemotherapy that is used in the myeloproliferative form of CMML to reduce cell numbers. Decitabine/cedazuridine (Inqovi) is a fixed-dosed combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) that was approved for use in the United States in July 2020.Hematopoietic stem cell transplantation remains the only curative treatment for CMML. However, due to the late age of onset and presence of other illnesses, this form of treatment is often not possible. Epidemiology There have been few individual epidemiological studies of CMML, due to the difficulty in the disease classification. CMML has an estimated incidence of less than 1 per 100,000 persons per year. The median age of diagnosis is 65–75. CMML has a propensity for males rather than females, at a ratio of 1.5–3:1. References == External links ==

Anhedonia

Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researchers to refer to reduced motivation, reduced anticipatory pleasure (wanting), reduced consummatory pleasure (liking), and deficits in reinforcement learning. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), anhedonia is a component of depressive disorders, substance-related disorders, psychotic disorders, and personality disorders, where it is defined by either a reduced ability to experience pleasure, or a diminished interest in engaging in pleasurable activities. While the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) does not explicitly mention anhedonia, the depressive symptom analogous to anhedonia as described in the DSM-5 is a loss of interest or pleasure. Definition While anhedonia was originally defined in 1896 by Théodule-Armand Ribot as the reduced ability to experience pleasure, it has been used to refer to deficits in multiple facets of reward. Re-conceptualizations of anhedonia highlight the independence of "wanting" and "liking". "Wanting" is a component of anticipatory positive affect, mediating both the motivation (i.e. incentive salience) to engage with reward, as well as the positive emotions associated with anticipating a reward. "Liking", on the other hand, is associated with the pleasure derived from consuming a reward. The consciousness of reward-related processes has also been used to categorize reward in the context of anhedonia, as studies comparing implicit behavior versus explicit self-reports demonstrate a dissociation of the two. Learning has also been proposed as an independent facet of reward that may be impaired in conditions associated with anhedonia, but empirical evidence dissociating learning from either "liking" or "wanting" is lacking.Anhedonia has also been used to refer to "affective blunting", "restricted range of affect", "emotional numbing", and "flat affect", particularly in the context of post-traumatic stress disorders. In PTSD patients, scales measuring these symptoms correlate strongly with scales that measure more traditional aspects of anhedonia, supporting this association. Causes Studies in clinical populations, healthy populations, and animal models have implicated a number of neurobiological substrates in anhedonia. Regions implicated in anhedonia include the prefrontal cortex as a whole, particularly the orbitofrontal cortex (OFC), the striatum, amygdala, anterior cingulate cortex (ACC), hypothalamus, and ventral tegmental area (VTA). Neuroimaging studies in humans have reported that deficits in consummatory aspects of reward are associated with abnormalities in the ventral striatum and medial prefrontal cortex, while deficits in anticipatory aspects of reward are related to abnormalities in hippocampal, dorsal ACC and prefrontal regions. These abnormalities are generally consistent with animal models, except for inconsistent findings with regard to the OFC. This inconsistency may be related to the difficulty in imaging the OFC due to its anatomical location, or the small number of studies performed on anhedonia; a number of studies have reported reduced activity in the OFC in schizophrenia and major depression, as well as a direct relationship between reduced activity and anhedonia. Researchers theorize that anhedonia may result from the breakdown in the brains reward system, involving the neurotransmitter dopamine. Anhedonia can be characterised as "impaired ability to pursue, experience and/or learn about pleasure, which is often, but not always accessible to conscious awareness".The conditions of akinetic mutism and negative symptoms are closely related. In akinetic mutism, a stroke or other lesion to the anterior cingulate cortex causes reduction in movement (akinetic) and speech (mutism). Occurrence Major depressive disorder Anhedonia occurs in roughly 70% of people with a major depressive disorder. Anhedonia is a core symptom of major depressive disorder; therefore, individuals experiencing this symptom can be diagnosed with depression, even in the absence of low/depressed mood. The Diagnostic and Statistical Manual of Mental Disorders (DSM) describes a "lack of interest or pleasure", but these can be difficult to discern given that people tend to become less interested in things which do not give them pleasure. The DSM criterion of weight loss is probably related, and many individuals with this symptom describe a lack of enjoyment of food. They can portray any of the non-psychotic symptoms and signs of depression. Schizophrenia Anhedonia is one of the negative symptoms of schizophrenia. Although five domains are usually used to classify negative symptoms, factor analysis of questionnaires yield two factors, with one including deficits in pleasure and motivation. People with schizophrenia retrospectively report experiencing fewer positive emotions than healthy individuals. However, "liking" or consummatory pleasure, is intact in people with schizophrenia, as they report experiencing the same degree of positive affect when presented with rewarding stimuli. Neuroimaging studies support this behavioral observation, as most studies report intact responses in the reward system (i.e. ventral striatum, VTA) to simple rewards. However, studies on monetary rewards sometimes report reduced responsiveness. More consistent reductions are observed with regard to emotional response during reward anticipation, which is reflected in a reduced responsiveness of both cortical and subcortical components of the reward system. Schizophrenia is associated with reduced positive prediction errors (a normal pattern of response to an unexpected reward), which a few studies have demonstrated to be correlated with negative symptoms. People with schizophrenia demonstrate impairment in reinforcement learnings tasks only when the task requires explicit learning, or is sufficiently complex. Implicit reinforcement learning, on the other hand, is relatively intact. These deficits may be related to dysfunction in the ACC, OFC and dlPFC leading to abnormal representation of reward and goals. Substance-related disorders Anhedonia is common in people who are dependent upon any one or more of a wide variety of drugs, including alcohol, opioids, and nicotine. Although anhedonia becomes less severe over time, it is a significant predictor of relapse. Post-traumatic stress disorder While PTSD is associated with reduced motivation, part of the anticipatory "wanting", it is also associated with elevated sensation seeking, and no deficits in physiological arousal, or self reported pleasure to positive stimuli. PTSD is also associated with blunted affect, which may be due to the high comorbidity with depression. Parkinsons disease Anhedonia occurs frequently in Parkinsons disease, with rates between 7%–45% being reported. Whether or not anhedonia is related to the high rates of depression in Parkinsons disease is unknown. Bipolar depression Anhedonia is also reported to appear in people with bipolar depression. Attention deficit hyperactivity disorder Anhedonia may be associated with ADHD. Impairments of dopaminergic and serotonergic function in the brain of those with ADHD result in dysregulation of reward processing which can lead to anhedonia. Sexual anhedonia Sexual anhedonia in males is also known as ejaculatory anhedonia. This condition means that the man will ejaculate with no accompanying sense of pleasure.The condition is most frequently found in males, but women can experience lack of pleasure when the body goes through the orgasm process as well. Sexual anhedonia may be caused by: Hyperprolactinaemia Hypoactive sexual desire disorder (HSDD), also called inhibited sexual desire Low levels of the hormone testosterone Spinal cord injury Multiple sclerosis Use of SSRI antidepressants or having used SSRI antidepressants in the past. Use (or previous use) of antidopaminergic neuroleptics (anti-psychotics) Fatigue Physical illnessIt is very uncommon that a neurological examination and blood tests can determine the cause of a specific case of sexual anhedonia. Patients may be prescribed sustained-release bupropion to aid in treatment, which has been shown to relieve sexual dysfunction even in patients without depression. Social anhedonia Definition Social anhedonia is defined as a disinterest in social contact and a lack of pleasure in social situations, and is characterized by social withdrawal. This characteristic typically manifests as an indifference to other people. In contrast to introversion, a nonpathological dimension of human personality, social anhedonia represents a deficit in the ability to experience pleasure. Additionally, social anhedonia differs from social anxiety in that social anhedonia is predominantly typified by diminished positive affect, while social anxiety is distinguished by both decreased positive affect and exaggerated negative affect.This trait is currently seen as a central characteristic, as well as a predictor, of schizophrenia spectrum disorders. Signs and symptoms Decreased ability to experience interpersonal pleasure Social withdrawal/isolation Decreased capacity for social contact and interaction Lack of close friends and intimate relationships, and decreased quality of those relationships Poor social adjustment Decreased positive affect Flat affect Depressed mood State-related anxiety Background and early clinical observation The term anhedonia is derived from the Greek an-, "without" and hēdonē, "pleasure". Interest in the nature of pleasure and its absence dates back to ancient Greek philosophers such as Epicurus. The symptoms of anhedonia were introduced to the realm of psychopathology in 1809 by John Haslam, who characterized a patient with schizophrenia as indifferent to "those objects and pursuits which formerly proved sources of delight and instruction". The concept was formally coined by Théodule-Armand Ribot and later used by psychiatrists Paul Eugen Bleuler and Emil Kraepelin to describe a core symptom of schizophrenia. In particular, Rado postulated that schizotypes, or individuals with the schizophrenic phenotype, have two key genetic deficits, one related to the ability to feel pleasure (anhedonia) and one related to proprioception. In 1962 Meehl furthered Rados theory through the introduction of the concept of schizotaxia, a genetically driven neural integrative defect thought to give rise to the personality type of schizotypy. Loren and Jean Chapman further distinguished between two types of anhedonia: physical anhedonia, or a deficit in the ability to experience physical pleasure, and social, or a deficit in the ability to experience interpersonal pleasure.Recent research suggests that social anhedonia may represent a prodrome of psychotic disorders. First-degree relatives of individuals with schizophrenia show elevated levels of social anhedonia, higher baseline scores of social anhedonia are associated with later development of schizophrenia. These findings provide support for the conjecture that it represents a genetic risk marker for schizophrenia-spectrum disorders. Additionally, elevated levels of social anhedonia in patients with schizophrenia have been linked to poorer social functioning. Socially anhedonic individuals perform worse on a number of neuropsychological tests than non-anhedonic participants, and show similar physiological abnormalities seen in patients with schizophrenia. Comorbidity Anhedonia is present in several forms of psychopathology. Depression Social anhedonia is observed in both depression and schizophrenia. However, social anhedonia is a state related to the depressive episode and the other is trait related to the personality construct associated with schizophrenia. These individuals both tend to score highly on self-report measures of social anhedonia. Blanchard, Horan, and Brown demonstrated that, although both the depression and the schizophrenia patient groups can look very similar in terms of social anhedonia cross-sectionally, over time as individuals with depression experience symptom remission, they show fewer signs of social anhedonia, while individuals with schizophrenia do not. Blanchard and colleagues (2011) found individuals with social anhedonia also had elevated rates of lifetime mood disorders including depression and dysthymia compared to controls. Social anxiety As mentioned above, social anxiety and social anhedonia differ in important ways. However, social anhedonia and social anxiety are also often comorbid. People with social anhedonia may display increased social anxiety and be at increased risk for social phobias and generalized anxiety disorder. It has yet to be determined what the exact relationship between social anhedonia and social anxiety is, and if one potentiates the other. Individuals with social anhedonia may display increased stress reactivity, meaning that they feel more overwhelmed or helpless in response to a stressful event compared to control subjects who experience the same type of stressor. This dysfunctional stress reactivity may correlate with hedonic capacity, providing a potential explanation for the increased anxiety symptoms experienced in people with social anhedonia. In an attempt to separate out social anhedonia from social anxiety, the Revised Social Anhedonia Scale didnt include items that potentially targeted social anxiety. However, more research must be conducted on the underlying mechanisms through which social anhedonia overlaps and interacts with social anxiety. The efforts of the "social processes" RDoC initiative will be crucial in differentiating between these components of social behavior that may underlie mental illnesses such as schizophrenia. Primary relevance in schizophrenia and schizophrenia spectrum disorders Social anhedonia is a core characteristic of schizotypy, which is defined as a continuum of personality traits that can range from normal to disordered and contributes to risk for psychosis and schizophrenia. Social anhedonia is a dimension of both negative and positive schizotypy. It involves social and interpersonal deficits, but is also associated with cognitive slippage and disorganized speech, both of which fall into the category of positive schizotypy. Not all people with schizophrenia display social anhedonia and likewise, people who have social anhedonia may never be diagnosed with a schizophrenia-spectrum disorder if they do not have the positive and cognitive symptoms that are most frequently associated with most schizophrenia-spectrum disorders.Social anhedonia may be a valid predictor of future schizophrenia-spectrum disorders; young adults with social anhedonia perform in a similar direction to schizophrenia patients in tests of cognition and social behavior, showing potential predictive validity. Social anhedonia usually manifests in adolescence, possibly because of a combination of the occurrence of critical neuronal development and synaptic pruning of brain regions important for social behavior and environmental changes, when adolescents are in the process of becoming individuals and gaining more independence. Treatment There is no validated treatment for social anhedonia. Future research should focus on genetic and environmental risk factors to home in on specific brain regions and neurotransmitters that may be implicated in social anhedonias cause and could be targeted with medication or behavioral treatments. Social support may also play a valuable role in the treatment of social anhedonia. Blanchard et al. found that a greater number of social supports, as well as a greater perceived social support network, were related to fewer schizophrenia-spectrum symptoms and to better general functioning within the social anhedonia group. So far, no medicine has been developed to specifically target anhedonia. Gender differences In the general population, males score higher than females on measures of social anhedonia. This sex difference is stable throughout time (from adolescence into adulthood) and is also seen in people with schizophrenia-spectrum disorders. These results may reflect a more broad pattern of interpersonal and social deficits seen in schizophrenia-spectrum disorders. On average, males with schizophrenia are diagnosed at a younger age, have more severe symptoms, worse treatment prognosis, and a decrease in overall quality of life compared to females with the disorder. These results, coupled with the sex difference seen in social anhedonia, outline the necessity for research on genetic and hormonal characteristics that differ between males and females, and that may increase risk or resilience for mental illnesses such as schizophrenia. Assessing social anhedonia There are several self-report psychometric measures of schizotypy which each contain subscales related to social anhedonia: Revised Social Anhedonia Scale—Chapman Psychosis Proneness Scales No Close Friends Subscale – Schizotypal Personality Questionnaire Introverted Anhedonia Subscale—Oxford–Liverpool Inventory of Feelings and Experiences Genetic components L.J. and J.P. Chapman were the first to discuss the possibility that social anhedonia may stem from a genetic vulnerability. The disrupted in schizophrenia 1 (DISC1) gene has been consistently associated with risk for, and cause of, schizophrenia-spectrum disorders and other mental illnesses. More recently, DISC1 has been associated with social anhedonia within the general population. Tomppo identified a specific DISC1 allele that is associated with an increase in characteristics of social anhedonia. They also identified a DISC1 allele associated with decreased characteristics of social anhedonia, that was found to be preferentially expressed in women. More research needs to be conducted, but social anhedonia may be an important intermediate phenotype (endophenotype) between genes associated with risk for schizophrenia and phenotype of the disorder. Neurobiological correlates Researchers studying the neurobiology of social anhedonia posit that this trait may be linked to dysfunction of reward-related systems in the brain. This circuitry is critical for the sensation of pleasure, the computation of reward benefits and costs, determination of the effort required to obtain a pleasant stimulus, deciding to obtain that stimulus, and increasing motivation to obtain the stimulus. In particular, the ventral striatum and areas of the prefrontal cortex (PFC), including the orbitofrontal cortex (OFC) and dorsolateral (dl) PFC, are critically involved in the experience of pleasure and the hedonic perception of rewards. With regards to neurotransmitter systems, opioid, gamma-Aminobutyric acid and endocannabinoid systems in the nucleus accumbens, ventral pallidum, and OFC mediate the hedonic perception of rewards. Activity in the PFC and ventral striatum have been found to be decreased in anhedonic individuals with major depressive disorder (MDD) and schizophrenia. However, schizophrenia may be less associated with decreased hedonic capacity and more with deficient reward appraisal. Specific musical anhedonia Recent studies have found people who do not have any issue processing musical tones or beat, yet receive no pleasure from listening to music. Specific musical anhedonia is distinct from melophobia, the fear of music. See also Avolition Dysthymia References External links Anhedonia – Bipolar Disorder Symptoms No Pleasure, No Reward

Pulled elbow

A pulled elbow, also known as a radial head subluxation, is when the ligament that wraps around the radial head slips off. Often a child will hold their arm against their body with the elbow slightly bent. They will not move the arm as this results in pain. Touching the arm, without moving the elbow, is usually not painful.A pulled elbow typically results from a sudden pull on an extended arm. This may occur when lifting or swinging a child by the arms. The underlying mechanism involves slippage of the annular ligament off of the head of the radius followed by the ligament getting stuck between the radius and humerus. Diagnosis is often based on symptoms. X-rays may be done to rule out other problems.Prevention is by avoiding potential causes. Treatment is by reduction. Moving the forearm into a palms down position with straightening at the elbow appears to be more effective than moving it into a palms up position followed by bending at the elbow. Following a successful reduction the child should return to normal within a few minutes. A pulled elbow is common. It generally occurs in children between the ages of 1 and 4 years old, though it can happen up to 7 years old. Signs and symptoms Symptoms include: The child stops using the arm, which is held in extension (or slightly bent) and palm down. Minimal swelling. All movements are permitted except supination. Caused by longitudinal traction with the wrist in pronation, although in a series only 51% of people were reported to have this mechanism, with 22% reporting falls, and patients less than 6 months of age noted to have the injury after rolling over in bed. Cause This injury has also been reported in babies younger than six months and in older children up to the preteen years. There is a slight predilection for this injury to occur in girls and in the left arm. The classic mechanism of injury is longitudinal traction on the arm with the wrist in pronation, as occurs when the child is lifted up by the wrist. There is no support for the common assumption that a relatively small head of the radius as compared to the neck of the radius predisposes the young to this injury. Pathophysiology The distal attachment of the annular ligament covering the radial head is weaker in children than in adults, allowing it to be more easily torn. The older child will usually point to the dorsal aspect of the proximal forearm when asked where it hurts. This may mislead one to suspect a buckle fracture of the proximal radius. There is no tear in the soft tissue (probably due to the pliability of young connective tissues).The forearm contains two bones: the radius and the ulna. These bones are attached to each other both at the proximal, or elbow, end and also at the distal, or wrist, end. Among other movements, the forearm is capable of pronation and supination, which is to say rotation about the long axis of the forearm. In this movement the ulna, which is connected to the humerus by a simple hinge-joint, remains stationary, while the radius rotates, carrying the wrist and hand with it. To allow this rotation, the proximal (elbow) end of the radius is held in proximity to the ulna by a ligament known as the annular ligament. This is a circular ligamentous structure within which the radius is free, with constraints existing elsewhere in the forearm, to rotate. The proximal end of the radius in young children is conical, with the wider end of the cone nearest the elbow. With the passage of time the shape of this bone changes, becoming more cylindrical but with the proximal end being widened.If the forearm of a young child is pulled, it is possible for this traction to pull the radius into the annular ligament with enough force to cause it to be jammed therein. This causes significant pain, partial limitation of flexion/extension of the elbow and total loss of pronation/supination in the affected arm. The situation is rare in adults, or in older children, because the changing shape of the radius associated with growth prevents it. Diagnosis Diagnosis is often based on symptoms. X-rays may be done to rule out other problems. Treatment To resolve the problem, the affected arm is moved in a way that causes the joint to move back into a normal position. The two main methods are hyperpronation and a combination of supination and flexion. Hyperpronation has a higher success rate and is less painful than a supination-flexion maneuver. References == External links ==

Nevus

Nevus (plural nevi) is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from nævus, which is Latin for "birthmark"; however, a nevus can be either congenital (present at birth) or acquired. Common terms, including mole, birthmark, and beauty mark, are used to describe nevi, but these terms do not distinguish specific types of nevi from one another. Classification The term nevus is applied to a number of conditions caused by neoplasias and hyperplasias of melanocytes, as well as a number of pigmentation disorders, both hypermelanotic (containing increased melanin, the pigment responsible for skin color) and hypomelanotic (containing decreased melanin). Suspicious skin moles which are multi-colored or pink may be a finding in skin cancer. Increased melanin Usually acquired Melanocytic nevus Melanocytic nevi can be categorized based on the location of melanocytic cellsJunctional: epidermis Intradermal: dermis Compound: epidermis and dermis Atypical (dysplastic) nevus: This type of nevus must be diagnosed based on histological features. Clinically, atypical nevi are characterized by variable pigmentation and irregular borders. Beckers nevus Blue nevus (rarely congenital): A classic blue nevus is usually smaller than 1 cm, flat, and blue-black in color. Horis nevus Nevus spilus (speckled lentiginous nevus): This lesion includes dark speckles within a tan-brown background. Pigmented spindle cell nevus Spitz nevus Zosteriform lentiginous nevus Usually congenital Congenital melanocytic nevus These nevi are often categorized based on size, however, the lesions usually grow in proportion to the body over time, so the category may change over an individuals life. This categorization is important because large congenital melanocytic nevi are associated with an increased risk of melanoma, a serious type of skin cancer.Small: <1.5 cm Medium: 1.5–19.9 cm Large: ≥ 20 cm Nevus of Ito Nevus of Ota Decreased melanin Acquired Nevus anemicus Congenital Nevus depigmentosus Additional types of nevi do not involve disorders of pigmentation or melanocytes. These additional nevi represent hamartomatous proliferations of the epithelium, connective tissue, and vascular malformations. Epidermal nevi These nevi represent excess growth of specific cells types found in the skin, including those that make up oil and sweat glands. Verrucous epidermal nevus Nevus sebaceous Nevus comedonicus Eccrine nevus Apocrine nevus Connective tissue nevi Connective tissue nevi represent abnormalities of collagen in the dermis, the deep layer of the skin. Collagenoma Elastoma Vascular nevi These nevi represent excess growth of blood vessels, including capillaries. Nevus simplex (nevus flammeus nuchae), also known as a stork bite or salmon patch. Intramucosal nevi An intramucosal nevus is a nevus within the mucosa as found in for example the mouth and genital areas. In the mouth, they are found most frequently on the hard palate. They are typically light brown and dome-shaped. Intramucosal nevi account for 64% of all reported case of oral nevi. Diagnosis Nevi are typically diagnosed clinically with the naked eye or using dermatoscopy. More advanced imaging tests are available for distinguishing melanocytic nevi from melanoma, including computerized dermoscopy and image analysis. The management of nevi depends on the type of nevus and the degree of diagnostic uncertainty. Some nevi are known to be benign, and may simply be monitored over time. Others may warrant more thorough examination and biopsy for histopathological examination (looking at a sample of skin under a microscope to detect unique cellular features). For example, a clinician may want to determine whether a pigmented nevus is a type of melanocytic nevus, dysplastic nevus, or melanoma as some of these skin lesions pose a risk for malignancy. The ABCDE criteria (asymmetry, border irregularity, color variegation, diameter > 6 mm, and evolution) are often used to distinguish nevi from melanomas in adults, while modified criteria (amelanosis, bleeding or bumps, uniform color, small diameter or de novo, and evolution) can be used when evaluating suspicious lesions in children. In addition to histopathological examination, some lesions may also warrant additional tests to aid in diagnosis, including special stains, immunohistochemistry, and electron microscopy. Typically, the nevi that exist since childhood are harmless. Differential diagnoses Hypermelanotic nevi must be differentiated from other types of pigmented skin lesions, including: Lentigo simplex Solar lentigo Café au lait macule Ink-spot lentigo Mucosal melanotic macule Mongolian spot (dermal melanocytosis) Management The management of a nevus depends on the specific diagnosis, however, the options for treatment generally include the following modalities: Observation Destruction Chemical peels Cryotherapy Dermabrasion Electrodessication Laser ablation Surgery The decision to observe or treat a nevus may depend on a number of factors, including cosmetic concerns, irritative symptoms (e.g., pruritus), ulceration, infection, and concern for potential malignancy. Syndromes The term nevus is included in the names of multiple dermatologic syndromes: Basal cell nevus syndrome Blue rubber bleb nevus syndrome Dysplastic nevus syndrome Epidermal nevus syndrome Linear nevus sebaceous syndrome Etymology A naevus may also be spelled nevus. The plural is nevi or naevi. The word is from nævus, Latin for "birthmark" and is correctly pronounced Nye-voos. See also Skin lesion References == External links ==

Proteinuria

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom may also be caused by other conditions). Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body. Signs and symptoms Proteinuria often causes no symptoms and it may only be discovered incidentally.Foamy urine is considered a cardinal sign of proteinuria, but only a third of people with foamy urine have proteinuria as the underlying cause. It may also be caused by bilirubin in the urine (bilirubinuria), retrograde ejaculation, pneumaturia (air bubbles in the urine) due to a fistula, or drugs such as pyridium. Causes There are three main mechanisms to cause proteinuria: Due to disease in the glomerulus Because of increased quantity of proteins in serum (overflow proteinuria) Due to low reabsorption at proximal tubule (Fanconi syndrome)Proteinuria can also be caused by certain biological agents, such as bevacizumab (Avastin) used in cancer treatment. Excessive fluid intake (drinking in excess of 4 litres of water per day) is another cause.Proteinuria may be a sign of renal (kidney) damage. Since serum proteins are readily reabsorbed from urine, the presence of excess protein indicates either an insufficiency of absorption or impaired filtration. People with diabetes may have damaged nephrons and develop proteinuria. The most common cause of proteinuria is diabetes, and in any person with proteinuria and diabetes, the cause of the underlying proteinuria should be separated into two categories: diabetic proteinuria versus the field. With severe proteinuria, general hypoproteinemia can develop which results in diminished oncotic pressure. Symptoms of diminished oncotic pressure may include ascites, edema and hydrothorax. Conditions with proteinuria Proteinuria may be a feature of the following conditions: Nephrotic syndromes (i.e. intrinsic kidney failure) Pre-eclampsia Eclampsia Toxic lesions of kidneys Amyloidosis Collagen vascular diseases (e.g. systemic lupus erythematosus) Dehydration Glomerular diseases, such as membranous glomerulonephritis, focal segmental glomerulonephritis, minimal change disease (lipoid nephrosis) Strenuous exercise Stress Benign orthostatic (postural) proteinuria Focal segmental glomerulosclerosis (FSGS) IgA nephropathy (i.e. Bergers disease) IgM nephropathy Membranoproliferative glomerulonephritis Membranous nephropathy Minimal change disease Sarcoidosis Alport syndrome Diabetes mellitus (diabetic nephropathy) Drugs (e.g. NSAIDs, nicotine, penicillamine, lithium carbonate, gold and other heavy metals, ACE inhibitors, antibiotics, or opiates (especially heroin) Fabry disease Infections (e.g. HIV, syphilis, hepatitis, poststreptococcal infection, urinary schistosomiasis) Aminoaciduria Fanconi syndrome in association with Wilson disease Hypertensive nephrosclerosis Interstitial nephritis Sickle cell disease Hemoglobinuria Multiple myeloma Myoglobinuria Organ rejection: Ebola virus disease Nail–patella syndrome Familial Mediterranean fever HELLP syndrome Systemic lupus erythematosus Granulomatosis with polyangiitis Rheumatoid arthritis Glycogen storage disease type 1 Goodpasture syndrome Henoch–Schönlein purpura A urinary tract infection which has spread to the kidney(s) Sjögren syndrome Post-infectious glomerulonephritis Living kidney donor Polycystic kidney disease Bence–Jones proteinuria Amyloidosis Pre-malignant plasma cell dyscrasias: Monoclonal gammopathy of undetermined significance Smoldering multiple myeloma Malignant plasma cell dyscrasias Multiple myeloma Waldenströms macroglobulinemia Other malignancies Chronic lymphocytic leukemia Rare cases of other Lymphoid leukemias Rare cases of Lymphomas Pathophysiology Protein is the building block of all living organisms. When kidneys are functioning properly by filtering the blood, they distinguish the proteins from the wastes which were previously present together in the blood. Thereafter, kidneys retain or reabsorb the filtered proteins and return them to the circulating blood while removing wastes by excreting them in the urine. Whenever the kidney is compromised, their ability to filter the blood by differentiating protein from the waste, or retaining the filtered protein then returning which back to the body, is damaged. As a result, there is a significant amount of protein to be discharged along with waste in the urine that makes the concentration of proteins in urine high enough to be detected by medical machine.Medical testing equipment has improved over time, and as a result tests are better able to detect smaller quantities of protein. Protein in urine is considered normal as long as the value remains within the normal reference range. Variation exists between healthy patients, and it is generally considered harmless for the kidney to fail to retain a few proteins in the blood, letting those protein discharge from the body through urine. Albumin and immunoglobins Albumin is a protein produced by the liver which makes up roughly 50%-60% of the proteins in the blood while the other 40%-50% are proteins other than albumin, such as immunoglobins. This is why the concentration of albumin in the urine is one of the single sensitive indicators of kidney disease, particularly for those with diabetes or hypertension, compared to routine proteinuria examination.As the loss of proteins from the body progresses, the suffering will gradually become symptomatic.The exception applies to the scenario when theres an overproduction of proteins in the body, in which the kidney is not to blame. Diagnosis Conventionally, proteinuria is diagnosed by a simple dipstick test, although it is possible for the test to give a false negative reading, even with nephrotic range proteinuria if the urine is dilute. False negatives may also occur if the protein in the urine is composed mainly of globulins or Bence Jones proteins because the reagent on the test strips, bromophenol blue, is highly specific for albumin. Traditionally, dipstick protein tests would be quantified by measuring the total quantity of protein in a 24-hour urine collection test, and abnormal globulins by specific requests for protein electrophoresis. Trace results may be produced in response to excretion of Tamm–Horsfall mucoprotein. More recently developed technology detects human serum albumin (HSA) through the use of liquid crystals (LCs). The presence of HSA molecules disrupts the LCs supported on the AHSA-decorated slides thereby producing bright optical signals which are easily distinguishable. Using this assay, concentrations of HSA as low as 15 µg/mL can be detected.Alternatively, the concentration of protein in the urine may be compared to the creatinine level in a spot urine sample. This is termed the protein/creatinine ratio. The 2005 UK Chronic Kidney Disease guidelines state that protein/creatinine ratio is a better test than 24-hour urinary protein measurement. Proteinuria is defined as a protein/creatinine ratio greater than 45 mg/mmol (which is equivalent to albumin/creatinine ratio of greater than 30 mg/mmol or approximately 300 mg/g) with very high levels of proteinuria having a ratio greater than 100 mg/mmol.Protein dipstick measurements should not be confused with the amount of protein detected on a test for microalbuminuria which denotes values for protein for urine in mg/day versus urine protein dipstick values which denote values for protein in mg/dL. That is, there is a basal level of proteinuria that can occur below 30 mg/day which is considered non-pathology. Values between 30 and 300 mg/day are termed microalbuminuria which is considered pathologic. Urine protein lab values for microalbumin of >30 mg/day correspond to a detection level within the "trace" to "1+" range of a urine dipstick protein assay. Therefore, positive indication of any protein detected on a urine dipstick assay obviates any need to perform a urine microalbumin test as the upper limit for microalbuminuria has already been exceeded. Analysis It is possible to analyze urine samples in determining albumin, hemoglobin and myoglobin with an optimized MEKC method. Treatment Treating proteinuria mainly needs proper diagnosis of the cause. The most common cause is diabetic nephropathy; in this case, proper glycemic control may slow the progression. Medical management consists of angiotensin converting enzyme (ACE) inhibitors, which are typically first-line therapy for proteinuria. In patients whose proteinuria is not controlled with ACE inhibitors, the addition of an aldosterone antagonist (i.e., spironolactone) or angiotensin receptor blocker (ARB) may further reduce protein loss. Caution must be used if these agents are added to ACE inhibitor therapy due to the risk of hyperkalemia. Proteinuria secondary to autoimmune disease should be treated with steroids or steroid-sparing agent plus the use of ACE inhibitors. See also Albuminuria Microalbuminuria List of terms associated with diabetes Protein toxicity Major urinary proteins UPCR References == External links ==

Dysfunction

Dysfunction can refer to: Abnormality (behavior) Dysfunctional family Sexual dysfunction Dysfunction (album), an album by the rock band Staind Manifest and latent functions and dysfunctions (sociological theory) Measurement dysfunction See also Malfunction (disambiguation)

Onycholysis

Onycholysis is a common medical condition characterized by the painless detachment of the nail from the nail bed, usually starting at the tip and/or sides. On the hands, it occurs particularly on the ring finger but can occur on any of the fingernails. It may also happen to toenails. Onycholysis can occur in many conditions, including psoriasis. In thyrotoxicosis, it is thought to be due to sympathetic overactivity. It may also be seen in infections or trauma. Causes Unknown Trauma, excessive manicuring Infection: especially fungal Skin disease: psoriasis, dermatitis Impaired peripheral circulation, e.g. Raynauds syndrome Systemic disease: hyperthyroidism, hypothyroidism, reactive arthritis, porphyria cutanea tarda Reaction to detergents (e.g. washing dishes with bare hands, using detergent-based shampoos or soaps). Patients with hepatocellular dysfunction may develop hair-thinning or hair loss and nail changes such as clubbing, leukonychia (whitening), or onycholysis, affecting the nails of the hands and feet. Onychomycosis (tinea) It is common in ballet dancers Chemotherapy (cytotoxic agents like taxanes, vinca alkaloids and others) Chronic Renal Failure Treatment Most instances of onycholysis without a clear cause will heal spontaneously within a few weeks. The most commonly recommended treatment is to keep the nail dry as much as possible and allow the nail to slowly reattach. Trimming away as much loose nail as can be done comfortably will prevent the nail from being pried upwards. Cleaning under the nail is not recommended as this only serves to separate the nail further. Bandages are also to be avoided. When kept dry and away from further trauma, the nail will reattach from the base upward (i.e., from proximal to distal).The aim of treatement is also to eliminate onychomycosis that is a major cause of onycholysis .Anti-biotics like Terbinafin and itraconazole in the form of oral pills should be given for 6 to 8 weeks. If the underlying cause of the condition is not found and the nail continues to detach despite conservative treatment, the nail bed may begin to form a granular layer of abnormal cells on its surface. After six months of detachment, this layer is likely to prevent the adhesion of any new nail tissue, possibly leading to permanent deformity. Etymology The word onycholysis comes from onycho-, from Ancient Greek ὄνυξ ónuks nail, and Ancient Greek λύσις lúsis lysis/disintegration. See also List of cutaneous conditions Plummers nail References == External links ==

Agoraphobia

Agoraphobia is a mental and behavioral disorder, specifically an anxiety disorder characterized by symptoms of anxiety in situations where the person perceives their environment to be unsafe with no easy way to escape. These situations can include open spaces, public transit, shopping centers, crowds and queues, or simply being outside their home on their own. Being in these situations may result in a panic attack. Those affected will go to great lengths to avoid these situations. In severe cases people may become completely unable to leave their homes.Agoraphobia is believed to be due to a combination of genetic and environmental factors. The condition often runs in families, and stressful or traumatic events such as the death of a parent or being attacked may be a trigger. In the DSM-5 agoraphobia is classified as a phobia along with specific phobias and social phobia. Other conditions that can produce similar symptoms include separation anxiety, post-traumatic stress disorder, and major depressive disorder. The diagnosis of agoraphobia has been shown to be comorbid with depression, substance abuse, and suicide ideation.Without treatment it is uncommon for agoraphobia to resolve. Treatment is typically with a type of counselling called cognitive behavioral therapy (CBT). CBT results in resolution for about half of people. In some instances those with a diagnosis of agoraphobia have reported taking benzodiazepines and antipsychotics augmentation. Agoraphobia affects about 1.7% of adults. Women are affected about twice as often as men. The condition often begins in early adulthood and becomes less common in old age. It is rare in children. Etymology The term "agoraphobia" was coined in German in 1871 by pioneering German psychologist Karl Friedrich Otto Westphal, 1833–1890, in his article "Die Agoraphobie, eine neuropathische Erscheinung." Archiv für Psychiatrie und Nervenkrankheiten, Berlin, 1871–72; 3: 138–161. It is derived from Greek ἀγορά, agorā́, meaning a "place of assembly" or "market-place" and -φοβία, -phobía, meaning "fear". Signs and symptoms Agoraphobia is a condition where individuals become anxious in unfamiliar environments or where they perceive that they have little control. Triggers for this anxiety may include wide-open spaces, crowds (social anxiety), or traveling (even short distances). Agoraphobia is often, but not always, compounded by a fear of social embarrassment, as the agoraphobic fears the onset of a panic attack and appearing distraught in public. Most of the time they avoid these areas and stay in the comfort of their haven, usually their home.Agoraphobia is also defined as "a fear, sometimes terrifying, by those who have experienced one or more panic attacks". In these cases, the patient is fearful of a particular place because they have experienced a panic attack at the same location at a previous time. Fearing the onset of another panic attack, the patient is fearful or even avoids a location. Some refuse to leave their homes even in medical emergencies because the fear of being outside of their comfort areas is too great.The person with this condition can sometimes go to great lengths to avoid the locations where they have experienced the onset of a panic attack. Agoraphobia, as described in this manner, is actually a symptom professionals check when making a diagnosis of panic disorder. Other syndromes like obsessive compulsive disorder or post-traumatic stress disorder can also cause agoraphobia. Essentially, any irrational fear that keeps one from going outside can cause the syndrome.People with agoraphobia may experience temporary separation anxiety disorder when certain other individuals of the household depart from the residence temporarily, such as a parent or spouse, or when they are left home alone. Such temporary conditions can result in an increase in anxiety or a panic attack or feeling the need to separate themselves from family or maybe friends.People with agoraphobia sometimes fear waiting outside for long periods of time; that symptom can be called "macrophobia". Panic attacks Agoraphobia patients can experience sudden panic attacks when traveling to places where they fear they are out of control, help would be difficult to obtain, or they could be embarrassed. During a panic attack, epinephrine is released in large amounts, triggering the bodys natural fight-or-flight response. A panic attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes. Symptoms of a panic attack include palpitations, rapid heartbeat, sweating, trembling, nausea, vomiting, dizziness, tightness in the throat, and shortness of breath. Many patients report a fear of dying, fear of losing control of emotions, or fear of losing control of behaviors. Causes Agoraphobia is believed to be due to a combination of genetic and environmental factors. The condition often runs in families, and stressful or traumatic events such as the death of a parent or being attacked may be a trigger.Research has uncovered a link between agoraphobia and difficulties with spatial orientation. Individuals without agoraphobia are able to maintain balance by combining information from their vestibular system, their visual system, and their proprioceptive sense. A disproportionate number of agoraphobics have weak vestibular function and consequently rely more on visual or tactile signals. They may become disoriented when visual cues are sparse (as in wide-open spaces) or overwhelming (as in crowds). Likewise, they may be confused by sloping or irregular surfaces. In a virtual reality study, agoraphobics showed impaired processing of changing audiovisual data in comparison with subjects without agoraphobia. Substance-induced Chronic use of tranquilizers and sleeping pills such as benzodiazepines has been linked to onset of agoraphobia. In 10 patients who had developed agoraphobia during benzodiazepine dependence, symptoms abated within the first year of assisted withdrawal. Similarly, alcohol use disorders are associated with panic with or without agoraphobia; this association may be due to the long-term effects of alcohol consumption causing a distortion in brain chemistry. Tobacco smoking has also been associated with the development and emergence of agoraphobia, often with panic disorder; it is uncertain how tobacco smoking results in anxiety-panic with or without agoraphobia symptoms, but the direct effects of nicotine dependence or the effects of tobacco smoke on breathing have been suggested as possible causes. Self-medication or a combination of factors may also explain the association between tobacco smoking and agoraphobia and panic. Attachment theory Some scholars have explained agoraphobia as an attachment deficit, i.e., the temporary loss of the ability to tolerate spatial separations from a secure base. Recent empirical research has also linked attachment and spatial theories of agoraphobia. Spatial theory In the social sciences, a perceived clinical bias exists in agoraphobia research. Branches of the social sciences, especially geography, have increasingly become interested in what may be thought of as a spatial phenomenon. One such approach links the development of agoraphobia with modernity. Factors considered contributing to agoraphobia within modernity are the ubiquity of cars and urbanization. These have helped develop the expansion of public space and the contraction of private space, thus creating in the minds of agoraphobia-prone people a tense, unbridgeable gulf between the two. Evolutionary psychology An evolutionary psychology view is that the more unusual primary agoraphobia without panic attacks may be due to a different mechanism from agoraphobia with panic attacks. Primary agoraphobia without panic attacks may be a specific phobia explained by it once having been evolutionarily advantageous to avoid exposed, large, open spaces without cover or concealment. Agoraphobia with panic attacks may be an avoidance response secondary to the panic attacks, due to fear of the situations in which the panic attacks occurred. Diagnosis Most people who present to mental health specialists develop agoraphobia after the onset of panic disorder. Agoraphobia is best understood as an adverse behavioral outcome of repeated panic attacks and subsequent anxiety and preoccupation with these attacks that leads to an avoidance of situations where a panic attack could occur. Early treatment of panic disorder can often prevent agoraphobia. Agoraphobia is typically determined when symptoms are worse than panic disorder, but also do not meet the criteria for other anxiety disorders such as depression. In rare cases where agoraphobics do not meet the criteria used to diagnose panic disorder, the formal diagnosis of agoraphobia without history of panic disorder is used (primary agoraphobia). Treatments Therapy Systematic desensitization can provide lasting relief to the majority of patients with panic disorder and agoraphobia. The disappearance of residual and sub-clinical agoraphobic avoidance, and not simply of panic attacks, should be the aim of exposure therapy. Many patients can deal with exposure easier if they are in the company of a friend on whom they can rely. Patients must remain in the situation until anxiety has abated because if they leave the situation, the phobic response will not decrease and it may even rise.A related exposure treatment is in vivo exposure, a cognitive behavioral therapy method, that gradually exposes patients to the feared situations or objects. This treatment was largely effective with an effect size from d = 0.78 to d = 1.34, and these effects were shown to increase over time, proving that the treatment had long-term efficacy (up to 12 months after treatment).Psychological interventions in combination with pharmaceutical treatments were overall more effective than treatments simply involving either CBT or pharmaceuticals. Further research showed there was no significant effect between using group CBT versus individual CBT.Cognitive restructuring has also proved useful in treating agoraphobia. This treatment involves coaching a participant through a dianoetic discussion, with the intent of replacing irrational, counterproductive beliefs with more factual and beneficial ones. Relaxation techniques are often useful skills for the agoraphobic to develop, as they can be used to stop or prevent symptoms of anxiety and panic.Videoconferencing psychotherapy (VCP) is an emerging modality used to treat various disorders in a remote method. Similar to traditional face-to-face interventions, VCP can be used to administer CBT. The use of VCP has been shown to be equally effective as face-to-face interventions at treating panic disorder and agoraphobia (PDA) and motivating the client to continue treatment. Medications Antidepressant medications most commonly used to treat anxiety disorders are mainly selective serotonin reuptake inhibitors. Benzodiazepines, monoamine oxidase inhibitor, and tricyclic antidepressants are also sometimes prescribed for treatment of agoraphobia. Antidepressants are important because some have anxiolytic effects. Antidepressants should be used in conjunction with exposure as a form of self-help or with cognitive behaviour therapy. A combination of medication and cognitive behaviour therapy is sometimes the most effective treatment for agoraphobia.Benzodiazepines and other anxiolytic medications such as alprazolam and clonazepam are used to treat anxiety and can also help control the symptoms of a panic attack. Alternative medicine Eye movement desensitization and reprocessing (EMDR) has been studied as a possible treatment for agoraphobia, with poor results. As such, EMDR is only recommended in cases where cognitive-behavioral approaches have proven ineffective or in cases where agoraphobia has developed following trauma.Many people with anxiety disorders benefit from joining a self-help or support group (telephone conference-call support groups or online support groups being of particular help for completely housebound individuals). Sharing problems and achievements with others, as well as sharing various self-help tools, are common activities in these groups. In particular, stress management techniques and various kinds of meditation practices and visualization techniques can help people with anxiety disorders calm themselves and may enhance the effects of therapy, as can service to others, which can distract from the self-absorption that tends to go with anxiety problems. Also, preliminary evidence suggests aerobic exercise may have a calming effect. Since caffeine, certain illicit drugs, and even some over-the-counter cold medications can aggravate the symptoms of anxiety disorders, they should be avoided. Epidemiology Agoraphobia occurs about twice as commonly among women as it does in men.Panic disorder with or without agoraphobia affects roughly 5.1% of Americans, and about 1/3 of this population with panic disorder have co-morbid agoraphobia. It is uncommon to have agoraphobia without panic attacks, with only 0.17% of people with agoraphobia not presenting panic disorders as well. Society and culture Notable cases See also Hikikomori List of phobias Phobia References This article incorporates public domain material from websites or documents of the National Institute of Mental Health. External links Agoraphobia at Curlie

Immunodeficiency

Immunodeficiency, also known as immunocompromisation, is a state in which the immune systems ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patients immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID. In clinical settings, immunosuppression by some drugs, such as steroids, can either be an adverse effect or the intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti-rejection measure and in patients with an overactive immune system, as in autoimmune diseases. Some people are born with intrinsic defects in their immune system, or primary immunodeficiency.A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised individual may particularly be vulnerable to opportunistic infections, in addition to normal infections that could affect anyone. It also decreases cancer immunosurveillance, in which the immune system scans the bodys cells and kills neoplastic ones. They are also more susceptible to infectious diseases owing to reduced protection afforded by vaccines. Types By affected component Humoral immune deficiency (including B cell deficiency or dysfunction), with signs or symptoms depending on the cause, but generally include signs of hypogammaglobulinemia (decrease of one or more types of antibodies) with presentations including repeated mild respiratory infections, and/or agammaglobulinemia (lack of all or most antibody production) which results in frequent severe infections and is often fatal. T cell deficiency, often causes secondary disorders such as acquired immune deficiency syndrome (AIDS). Granulocyte deficiency, including decreased numbers of granulocytes (called as granulocytopenia or, if absent, agranulocytosis) such as of neutrophil granulocytes (termed neutropenia). Granulocyte deficiencies also include decreased function of individual granulocytes, such as in chronic granulomatous disease. Asplenia, where there is no function of the spleen Complement deficiency is where the function of the complement system is deficientIn reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary). Primary or secondary The distinction between primary versus secondary immunodeficiencies is based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it. Primary immunodeficiency A number of rare diseases feature a heightened susceptibility to infections from childhood onward. Primary Immunodeficiency is also known as congenital immunodeficiencies. Many of these disorders are hereditary and are autosomal recessive or X-linked. There are over 95 recognised primary immunodeficiency syndromes; they are generally grouped by the part of the immune system that is malfunctioning, such as lymphocytes or granulocytes.The treatment of primary immunodeficiencies depends on the nature of the defect, and may involve antibody infusions, long-term antibiotics and (in some cases) stem cell transplantation. The characteristics of lacking and/or impaired antibody functions can be related to illnesses such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency Secondary immunodeficiencies Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging, particular medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids) and environmental toxins like mercury and other heavy metals, pesticides and petrochemicals like styrene, dichlorobenzene, xylene, and ethylphenol. For medications, the term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term immunodeficiency generally refers solely to the adverse effect of increased risk for infection. Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly. Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism and hyperglycemia. Smoking, alcoholism and drug abuse also depress immune response. Heavy schedules of training and competition in athletes increases their risk of immune deficiencies. Diagnosis Patients with immune deficiencies can present with variable clinical phenotypes. This often translates into a significant delay in their diagnosis, and resultant patient morbidity. A structured approach on when to suspect an immunodeficiency and the initial investigations pathway is given in the publication by Grammatikos et al. Immunodeficiency and autoimmunity There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation. One example is common variable immunodeficiency (CVID) where multiple autoimmune diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia, and autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis, an autosomal recessive primary immunodeficiency, is another example. Low blood levels of red blood cells, white blood cells, and platelets, rashes, lymph node enlargement, and enlargement of the liver and spleen are commonly seen in these patients. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible. In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is caused by a decreased production of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena. Causes The cause of immunodeficiency varies depending on the nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions. Only for some genetic causes, the exact genes are known. Treatment Available treatment falls into two modalities: treating infections and boosting the immune system. Prevention of Pneumocystis pneumonia using trimethoprim/sulfamethoxazole is useful in those who are immunocompromised. In the early 1950s Immunoglobulin(Ig) was used by doctors to treat patients with primary immunodeficiency through intramuscular injection. Ig replacement therapy are infusions that can be either subcutaneous or intravenously administrated, resulting in higher Ig levels for about three to four weeks, although this varies with each patient. Prognosis Prognosis depends greatly on the nature and severity of the condition. Some deficiencies cause early mortality (before age one), others with or even without treatment are lifelong conditions that cause little mortality or morbidity. Newer stem cell transplant technologies may lead to gene based treatments of debilitating and fatal genetic immune deficiencies. Prognosis of acquired immune deficiencies depends on avoiding or treating the causative agent or condition (like AIDS). See also Acquired immune deficiency syndrome (AIDS) Immune disorder Autoimmune disease, immune response to self-proteins Allergy, immune response to harmless non-self proteins Histamine Immunosenescence, age-associated immune deficiency Steroids, commonly administered drugs like prednisone that suppress the immune system Human genetic enhancement Immune system Immunology References External links Immune Deficiency Foundation The European Society of Immunodeficiencies

Angiostrongyliasis

Angiostrongyliasis is an infection by a roundworm of the Angiostrongylus type. Symptoms may vary from none, to mild, to meningitis.Infection with Angiostrongylus cantonensis (rat lungworm) can occur after ingestion of raw or undercooked snails or slugs, and less likely unwashed fruits and vegetables. In humans, A. cantonensis is the most common cause of eosinophilic meningitis or meningoencephalitis. Frequently the infection will resolve without treatment or serious consequences, but in cases with a heavy load of parasites the infection can be so severe it can cause permanent damage to the central nervous system or death. Symptoms Infection first presents with severe abdominal pain, nausea, vomiting, and weakness, which gradually lessens and progresses to fever, and then to central nervous system (CNS) symptoms and severe headache and stiffness of the neck. CNS infection CNS symptoms begin with mild cognitive impairment and slowed reactions, and in a very severe form often progress to unconsciousness. Patients may present with neuropathic pain early in the infection. Eventually, severe infection will lead to ascending weakness, quadriparesis, areflexia, respiratory failure, and muscle atrophy, and will lead to death if not treated. Occasionally patients present with cranial nerve palsies, usually in nerves 7 and 8, and rarely larvae will enter ocular structures. Even with treatment, damage to the CNS may be permanent and result in a variety of negative outcomes depending on the location of the infection, and the patient may experience chronic pain as a result of infection. Eye invasion Symptoms of eye invasion include visual impairment, pain, keratitis, and retinal edema. Worms usually appear in the anterior chamber and vitreous and can sometimes be removed surgically. Incubation period The incubation period in humans is usually from 1 week to 1 month after infection, and can be as long as 47 days. This interval varies, since humans are accidental hosts and the life cycle does not continue predictably as it would in a rat. Cause Transmission Transmission of the parasite is usually from eating raw or undercooked snails or other vectors. Infection is also frequent from ingestion of contaminated water or unwashed salad that may contain small snails and slugs, or have been contaminated by them. Reservoirs Rats are the definitive host and the main reservoir for A. cantonensis, though other small mammals may also become infected. While Angiostrongylus can infect humans, humans do not act as reservoirs since the worm cannot reproduce in humans and therefore humans cannot contribute to their life cycle. Vectors Angiostrongylus cantonensis has many vectors among invertebrates, with the most common being several species of snails, including the giant African land snail (Achatina) in the Pacific islands and apple snails of the genus Pila in Thailand and Malaysia. The golden apple snail, Pomacea canaliculata, is the most important vector in areas of China. Freshwater prawns, crabs, or other paratenic, or transport, hosts can also act as vectors. Organism Morphology A. cantonensis is a nematode roundworm with 3 outer protective collagen layers, and a simple stomal opening or mouth with no lips or buccal cavity leading to a fully developed gastrointestinal tract. Males have a small copulatory bursa at the posterior. Females have a "barber pole" shape down the middle of the body, which is created by the twisting together of the intestine and uterine tubules. The worms are long and slender - males are 15.9–19 mm in length, and females are 21–25 mm in length. Life cycle The adult form of A. cantonensis resides in the pulmonary arteries of rodents, where it reproduces. After the eggs hatch in the arteries, larvae migrate up the pharynx and are then swallowed again by the rodent and passed in the stool. These first stage larvae then penetrate or are swallowed by snail intermediate hosts, where they transform into second stage larvae and then into third stage infective larvae. Humans and rats acquire the infection when they ingest contaminated snails or paratenic (transport) hosts including prawns, crabs, and frogs, or raw vegetables containing material from these intermediate and paratenic hosts. After passing through the gastrointestinal tract, the worms enter circulation. In rats, the larvae then migrate to the meninges and develop for about a month before migrating to the pulmonary arteries, where they fully develop into adults.Humans are incidental hosts; the larvae cannot reproduce in humans and therefore humans do not contribute to the A. cantonensis life cycle. In humans, the circulating larvae migrate to the meninges, but do not move on to the lungs. Sometimes the larvae will develop into the adult form in the brain and CSF, but they quickly die, inciting the inflammatory reaction that causes symptoms of infection. Diagnosis Diagnosis of Angiostrongyliasis is complicated due to the difficulty of presenting the angiostrongylus larvae themselves, and will usually be made based on the presence of eosinophilic meningitis and history of exposure to snail hosts. Eosinophilic meningitis is generally characterized as a meningitis with >10 eosinophils/μL in the CSF or at least 10% eosinophils in the total CSF leukocyte count. Occasionally worms found in the cerebrospinal fluid or surgically removed from the eye can be identified in order to diagnose Angiostrongyliasis. Lumbar puncture Lumbar puncture should always be done in cases of suspected meningitis. In cases of eosinophilc meningitis it will rarely produce worms even when they are present in the CSF, because they tend to cling to the end of nerves. Larvae are present in the CSF in only 1.9-10% of cases. However, as a case of eosinophilic meningitis progresses, intracranial pressure and eosinophil counts should rise. Increased levels of eosinophils in the CSF is a hallmark of the eosinophilic meningitis. Brain imaging Brain lesions, with invasion of both gray and white matter, can be seen on a CT or MRI. However MRI findings tend to be inconclusive, and usually include nonspecific lesions and ventricular enlargement. Sometimes a hemorrhage, probably produced by migrating worms, is present and of diagnostic value. Serology In patients with elevated eosinophils, serology can be used to confirm a diagnosis of angiostrongyliasis rather than infection with another parasite. There are a number of immunoassays that can aid in diagnosis, however serologic testing is available in few labs in the endemic area, and is frequently too non-specific. Some cross reactivity has been reported between A. cantonensis and trichinosis, making diagnosis less specific. The most definitive diagnosis always arises from the identification of larvae found in the CSF or eye, however due to this rarity a clinical diagnosis based on the above tests is most likely. Prevention There are public health strategies that can limit the transmission of A. cantonensis by limiting contact with infected vectors. Vector control may be possible, but has not been very successful in the past. Education to prevent the introduction of rats or snail vectors outside endemic areas is important to limit the spread of the disease. There are no vaccines in development for angiostrongyliasis. Recommendations for individuals To avoid infection when in endemic areas, travelers should: Avoid consumption of uncooked vectors, such as snails and freshwater prawns Avoid drinking water from open sources, which may have been contaminated by vectors Prevent young children from playing with or eating live snails Treatment Treatment of angiostrongyliasis is not well defined, but most strategies include a combination of anti-parasitics to kill the worms, steroids to limit inflammation as the worms die, and pain medication to manage the symptoms of meningitis. Anthelmintics Anthelmintics are often used to kill off the worms, however in some cases this may cause patients to worsen due to toxins released by the dying worms. Albendazole, ivermectin, mebendazole, and pyrantel are all commonly used, though albendazole is usually the drug of choice. Studies have shown that anthelmintic drugs may shorten the course of the disease and relieve symptoms. Therefore, anthelmintics are generally recommended, but should be administered gradually so as to limit the inflammatory reaction. Anti-inflammatories Anthelmintics should generally be paired with corticosteroids in severe infections to limit the inflammatory reaction to the dying parasites. Studies suggest that a two-week regimen of a combination of mebendazole and prednisolone significantly shortened the course of the disease and length of associated headaches without observed harmful side effects. Other studies suggest that albendazole may be more favorable, because it may be less like to incite an inflammatory reaction. Symptomatic treatment Symptomatic treatment is indicated for symptoms such as nausea, vomiting, headache, and in some cases, chronic pain due to nerve damage or muscle atrophy. Epidemiology A. cantonensis and its vectors are endemic to Southeast Asia and the Pacific Basin. The infection is becoming increasingly important as globalization allows it to spread to more locations, and as more travelers encounter the parasites. The parasites probably travel effectively through rats traveling as stowaways on ships, and through the introduction of snail vectors outside endemic areas.Although mostly found in Asia and the Pacific where asymptomatic infection can be as high as 88%, human cases have been reported in the Caribbean, where as much as 25% of the population may be infected. In the United States, cases have been reported in Hawaii, which is in the endemic area. The infection is now endemic in wildlife and a few human cases have also been reported in areas where the parasite was not originally endemic, such as New Orleans and Egypt. The disease has also arrived in Brazil, where there were 34 confirmed cases from 2006 to 2014, including one death. The giant African land snail, which can be a vector of the parasite, has been introduced to Brazil as an invasive species and is spreading the disease. There may be more undiagnosed cases, as Brazilian physicians are not familiar with the eosinophilic meningitis associated to angiostrongyliasis and misdiagnose it as bacterial or viral.The parasite is rarely seen outside of endemic areas, and in these cases patients generally have a history of travel to an endemic area. See also Schistosomiasis, a parasitic disease also spread by snails List of unusual deaths – lists Australian man Sam Ballard as dying from Angiostrongyliasis in 2018, as a result of eating a garden slug eight years earlier on a dare References Further reading "Parasites - Angiostrongyliasis (also known as Angiostrongylus Infection)". CDC. 2015-12-28. Retrieved 2017-04-04. "DPDx - Angiostrongyliasis". CDC. 2016-10-17. Retrieved 2017-04-04. Tabs for Parasite Biology, Image Gallery, Laboratory Diagnosis, and Treatment Information. == External links ==

Calcaneal spur

A calcaneal spur (also known as a heel spur) is a bony outgrowth from the calcaneal tuberosity (heel bone). Calcaneal spurs are typically detected by x-ray examination. It is a form of exostosis. When a foot is exposed to constant stress, calcium deposits build up on the bottom of the heel bone. Generally, this has no effect on a persons daily life. However, repeated damage can cause these deposits to pile up on each other, causing a spur-shaped deformity, called a calcaneal (or heel) spur.An inferior calcaneal spur is located on the inferior aspect of the calcaneus and is typically a response to plantar fasciitis over a period, but may also be associated with ankylosing spondylitis (typically in children). A posterior calcaneal spur develops on the back of the heel at the insertion of the Achilles tendon.An inferior calcaneal spur consists of a calcification of the calcaneus, which lies superior to the plantar fascia at the insertion of the plantar fascia. A posterior calcaneal spur is often large and palpable through the skin and may need to be removed as part of the treatment of insertional Achilles tendonitis. Signs and symptoms Major symptoms consist of pain in the region surrounding the spur, which typically increases in intensity after prolonged periods of rest. Patients may report heel pain to be more severe when waking up in the morning. Patients may not be able to bear weight on the affected heel comfortably. Running, walking, or lifting heavy weight may exacerbate the issue. Causes Plantar fasciitis is a common cause of calcaneal spurs. When stress is put on the plantar fascia ligament, it does not cause only plantar fasciitis, but causes a heel spur where the plantar fascia attaches to the heel bone. The considerations that affect plantar heel pain are the alignment of the foot with lower leg, foot and ankle mobility, strength and endurance of muscle. External influences on plantar heel pain are the amount of time spent on feet while exercising or standing, type of footwear used and type of floor surfaces.Calcaneal spur develops when proper care is not given to the foot and heels. People who are obese, have flat feet, or who often wear high-heeled shoes are most susceptible to heel spurs. Flat feet can potentially be attributed to the minimal amount of ankle dorsiflexion during stance phase of the gait cycle causing more tension on the plantar fascia. Diagnosis Spur outgrowths can be detected through physical exam followed by a lateral foot x-ray. Treatment It is often seen as a repetitive stress injury, and thus lifestyle modification is typically the basic course of management strategies. For example, a person should begin doing foot and calf workouts. Strong muscles in the calves and lower legs will help take the stress off the bone and prevent heel spurs. Icing the area is an effective way to get immediate pain relief. There are several means to get pain relief from plantar heel pain. Plantar heel pain can be a precursor to many pathologies of the foot. There is evidence that corticosteroid injections may reduce pain for up to one month after the injection, which can have an impact on the formation of calcaneal spurs. Side effects of corticosteroid injections includes peripheral nerve injury, plantar fascia rupture, and post injection flare, among others. Laser therapy, dry needling, and calcaneal taping are also utilized in treating plantar heel pain, however, there is not high quality evidence supporting the clinical usage of such modalities in reduction of pain. References External links Calcaneal spur at Curlie

Male infertility

Male infertility refers to a sexually mature males inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed. Age considerations There is a decrease in sperm concentration as men age: 90% of seminiferous tubules in men in their 20s and 30s contain spermatids, whereas men in their 40s and 50s have spermatids in 50% of their seminiferous tubules, and only 10% of seminiferous tubules from men aged > 80 years contain spermatids. In a random international sample of 11,548 men confirmed to be biological fathers by DNA paternity testing, the oldest father was found to be 66 years old at the birth of his child; the ratio of DNA-confirmed versus DNA-rejected paternity tests around that age is in agreement with the notion of general male infertility above age 65–66. Causes Factors relating to male infertility include: Immune infertility Antisperm antibodies (ASA) have been considered as infertility cause in around 10–30% of infertile couples. ASA production are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and acrosome reaction, impaired fertilization, influence on the implantation process, and impaired growth and development of the embryo. Risk factors for the formation of antisperm antibodies in men include the breakdown of the blood‑testis barrier, trauma and surgery, orchitis, varicocele, infections, prostatitis, testicular cancer, failure of immunosuppression and unprotected receptive anal or oral sex with men. Genetics Chromosomal anomalies and genetic mutations account for nearly 10–15% of all male infertility cases. Klinefelter syndrome One of the most commonly known causes of infertility is Klinefelter syndrome, which affects one in 500–1000 newborn males. Klinefelter syndrome is a chromosomal defect that occurs during gamete formation due to a non-disjunction error during cell division. Resulting in males having smaller testes, reducing the amount of testosterone and sperm production. Males with this syndrome carry an extra X chromosome (XXY), meaning they have 47 chromosomes compared to the normal 46 in each cell. This extra chromosome directly affects sexual development before birth and during puberty. A variation of Klinefelter syndrome is when some cells in an individual have the extra X chromosome but others do not, referred to as mosaic Klinefelter syndrome. The reduction of testosterone in the male body normally results in an overall decrease in the production of viable sperm for these individuals thereby forcing them to turn to fertility treatments to father children. Y chromosome deletions Y chromosomal infertility is a direct cause of male infertility due to its effects on sperm production, occurring in approximately one in 2000 males. Usually, affected men show no symptoms, although they may have smaller testes. Men with this condition may exhibit azoospermia (no sperm production), oligozoospermia (small number of sperm production), or they may produce abnormally shaped sperm (teratozoospermia). This case of infertility occurs during the development of gametes in the male. Where a normal healthy male will have both an X and a Y chromosome, affected males have genetic deletions in the Y chromosome. These deletions affect protein production that is vital for spermatogenesis. Studies have shown that this is an inherited trait; if a male is fathered by a man who also exhibited Y chromosome deletions then this trait will be passed down. These individuals are thereby "Y-linked". Daughters are not affected and cannot be carriers due to their lack of a Y chromosome. Other Age group 12–49 (Paternal age effect) Aneuploidy, an abnormal number of chromosomes Centriole Neoplasm, e.g. seminoma Idiopathic failure Cryptorchidism Trauma Hydrocele, particularly hydrocele testis Hypopituitarism in adults, and hypopituitarism untreated in children (resulting in growth hormone deficiency and proportionate dwarfism.) Mumps Malaria Testicular cancer Defects in USP26 in some cases Acrosomal defects affecting egg penetration Idiopathic oligospermia – unexplained sperm deficiencies account for 30% of male infertility. Pre-testicular causes Pre-testicular factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including: Varicocele Varicocele is a condition of swollen testicle veins.It is present in 15% of normal men and in about 40% of infertile men. It is present in up to 35% of cases of primary infertility and 69–81% of secondary infertility. Hypogonadotropic hypogonadism due to various causes Obesity increases the risk of hypogonadotropic hypogonadism. Animal models indicate that obesity causes leptin insensitivity in the hypothalamus, leading to decreased Kiss1 expression, which, in turn, alters the release of gonadotropin-releasing hormone (GnRH). Undiagnosed and untreated coeliac disease (CD). Coeliac men may have reversible infertility. Nevertheless, CD can present with several non-gastrointestinal symptoms that can involve nearly any organ system, even in the absence of gastrointestinal symptoms. Thus, the diagnosis may be missed, leading to a risk of long-term complications. In men, CD can reduce semen quality and cause immature secondary sex characteristics, hypogonadism and hyperprolactinaemia, which causes impotence and loss of libido. The giving of gluten free diet and correction of deficient dietary elements can lead to a return of fertility. It is likely that an effective evaluation for infertility would best include assessment for underlying celiac disease, both in men and women. Drugs, alcohol Strenuous riding (bicycle riding, horseback riding) Medications, including those that affect spermatogenesis such as chemotherapy, fluoxetine, anabolic steroids, cimetidine, spironolactone; those that decrease FSH levels such as phenytoin; those that decrease sperm motility such as sulfasalazine and nitrofurantoin Genetic abnormalities such as a Robertsonian translocation Tobacco smoking There is increasing evidence that the harmful products of tobacco smoking may damage the testicles and kill sperm, but their effect on male fertility is not clear. Some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes. DNA damage Common inherited variants in genes that encode enzymes employed in DNA mismatch repair are associated with increased risk of sperm DNA damage and male infertility. As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage. The damage manifests by DNA fragmentation and by the increased susceptibility to denaturation upon exposure to heat or acid, the features characteristic of apoptosis of somatic cells. These findings suggest that DNA damage is an important factor in male infertility. Epigenetic An increasing amount of recent evidence has been recorded documenting abnormal sperm DNA methylation in association with abnormal semen parameters and male infertility. Until recently, scientists have thought that epigenetic markers only affect the individual and are not passed down due to not changing the DNA. New studies suggest that environmental factors that changed an individuals epigenetic markers can be seen in their grandchildren, one such study demonstrating this through rats and fertility disruptors. Another study bred rats exposed to an endocrine disruptor, observing effects up to generation F5 including decreased sperm motility and decreased sperm count. These studies suggest that environmental factors that influence fertility can be felt for generations even without changing the DNA. Post-testicular causes Post-testicular factors decrease male fertility due to conditions that affect the male genital system after testicular sperm production and include defects of the genital tract as well as problems in ejaculation: Vas deferens obstruction Lack of Vas deferens, often related to genetic markers for cystic fibrosis Infection, e.g. prostatitis, male accessory gland infection Retrograde ejaculation Ejaculatory duct obstruction Hypospadias Impotence Diagnostic evaluations The diagnosis of infertility begins with a medical history and physical exam by a physician, physician assistant, or nurse practitioner. Typically two separate semen analyses will be required. The provider may order blood tests to look for hormone imbalances, medical conditions, or genetic issues. Medical history The history should include prior testicular or penile insults (torsion, cryptorchidism, trauma), infections (mumps orchitis, epididymitis), environmental factors, excessive heat, radiation, medications, and drug use (anabolic steroids, alcohol, smoking).Sexual habits, frequency and timing of intercourse, use of lubricants, and each partners previous fertility experiences are important.Loss of libido and headaches or visual disturbances may indicate a pituitary tumor.The past medical or surgical history may reveal thyroid or liver disease (abnormalities of spermatogenesis), diabetic neuropathy (retrograde ejaculation), radical pelvic or retroperitoneal surgery (absent seminal emission secondary to sympathetic nerve injury), or hernia repair (damage to the vas deferens or testicular blood supply).A family history may reveal genetic problems. Physical examination Usually, the patient disrobes completely and puts on a gown. The physician, physician assistant, or nurse practitioner will perform a thorough examination of the penis, scrotum, testicles, I vas deferens, spermatic cords, ejaculatory ducts, urethra, urinary bladder, anus and rectum. An orchidometer can measure testicular volume, which in turn is tightly associated with both sperm and hormonal parameters. A physical exam of the scrotum can reveal a varicocele, but the impact of detecting and surgically correct a varicocele on sperm parameters or overall male fertility is debated. Sperm sample Semen sample obtaining Semen sample obtaining is the first step in spermiogram. The optimal sexual abstinence for semen sample obtaining is of 2–7 days. The first way to obtain the semen sample is through masturbation, and the best place to obtain it is in the same clinic, as this way temperature changes during transport can be avoided, which can be lethal for some spermatozoa. A single semen sample is not determining for disease diagnosis, so two different samples have to be analyzed with an interval between them of seven days to three months, as sperm production is a cyclic process. It is prudent to ask about possible sample loss, as that could mask true results of spermiogram. To obtain the sample, a sterile plastic recipient is put directly inside, always no more than one hour before being studied. Conventional preservatives shouldnt be used, as they have chemical substances as lubricants or spermicides that could damage the sample. If preservatives have to be used, for cases of religious ethics in which masturbation is forbidden, a preservative with holes is used. In case of paraplegia it is possible to use mechanic tools or electroejaculation. The sample should never be obtained through coitus interruptus for several reasons: Some part of ejaculation could be lost. Bacterial contamination could happen. The acid vaginal pH could be deleterious for sperm motility.Also is very important to label the sample correctly the recipient with patient identification, date, hour, abstinence days, among other data required to be known. The volume of the semen sample (must be more than 1.5 ml), approximate number of total sperm cells, sperm motility/forward progression, and % of sperm with normal morphology are measured. It is possible to have hyperspermia (high volume more than 6 ml) or Hypospermia (low volume less than 0.5 ml). This is the most common type of fertility testing. Semen deficiencies are often labeled as follows: Oligospermia or oligozoospermia – decreased number of spermatozoa in semen Aspermia – complete lack of semen Hypospermia – reduced seminal volume Azoospermia – absence of sperm cells in semen Teratospermia – increase in sperm with abnormal morphology Asthenozoospermia – reduced sperm motility Necrozoospermia – all sperm in the ejaculate are dead Leucospermia – a high level of white blood cells in semen Normozoospermia or normospermia – It is a result of semen analysis that shows normal values of all ejaculate parameters by WHO but still there are chances of being infertile. This is also called as unexplained InfertilityThere are various combinations of these as well, e.g. Teratoasthenozoospermia, which is reduced sperm morphology and motility. Low sperm counts are often associated with decreased sperm motility and increased abnormal morphology, thus the terms "oligoasthenoteratozoospermia" or "oligospermia" can be used as a catch-all. Special obtaining Psychological inhibition– Psychotherapy – Intercourses with special preservatives without lubricants or spermicides. In case of religion limitations we should use a SCD, or Seminal Collection Device, such as preservatives with holes. – Drug stimulation – Percutaneous spermatozoa obtaining directly from epididymis, testes, etc. Neurological injury– Vibro-stimulation – Electro-stimulation Retrograde ejaculationThis type of ejaculation happens when there is a defect on prostate, so the sample is not ejaculated outside but to the bladder. So, in that case, what we have to do to obtain the sample is: – Intake bicarbonate, about 25 grams, the night before and the morning of the sample obtaining. This will neutralize acidic urine and will turn it alkaline, near semens pH, so spermatozoa can survive. – Before masturbation we have to urinate to empty the bladder. This must go to the first recipient. – Just after that, the subject has to masturbate and ejaculate, obtaining then a new urine sample with ejaculation that will be stored on the second recipient. – Finally we have to obtain the next urine, 2nd urine, for potential ejaculation fraction, which will be stored in the third recipient. This may contain the most important fraction. Blood sample Common hormonal test include determination of FSH and testosterone levels. A blood sample can reveal genetic causes of infertility, e.g. Klinefelter syndrome, a Y chromosome microdeletion, or cystic fibrosis. Ultrasonography Scrotal ultrasonography is useful when there is a suspicion of some particular diseases. It may detect signs of testicular dysgenesis, which is often related to an impaired spermatogenesis and to a higher risk of testicular cancer. Scrotum ultrasonography may also detect testicular lesions suggestive of malignancy. A decreased testicular vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions such as lymphoma and leukemia. Doppler ultrasonography useful in assessing venous reflux in case of a varicocele, when palpation is unreliable or in detecting recurrence or persistence after surgery, although the impact of its detection and surgical correction on sperm parameters and overall fertility is debated.Dilation of the head or tail of the epididymis is suggestive of obstruction or inflammation of the male reproductive tract. Such abnormalities are associated with abnormalities in sperm parameters, as are abnormalities in the texture of the epididymis. Scrotal and transrectal ultrasonography (TRUS) are useful in detecting uni- or bilateral congenital absence of the vas deferens (CBAVD), which may be associated with abnormalities or agenesis of the epididymis, seminal vesicles or kidneys, and indicate the need for testicular sperm extraction. TRUS plays a key role in assessing azoospermia caused by obstruction, and detecting distal CBAVD or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied. Prevention Some strategies suggested or proposed for avoiding male infertility include the following: Avoiding smoking as it damages sperm DNA Avoiding heavy marijuana and alcohol use. Avoiding excessive heat to the testes. Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more). Wearing a protective cup and jockstrap to protect the testicles, in any sport such as baseball, football, cricket, lacrosse, hockey, softball, paintball, rodeo, motorcross, wrestling, soccer, karate or other martial arts or any sport where a ball, foot, arm, knee or bat can come into contact with the groin. Diet: Healthy diets (i.e. the Mediterranean diet) rich in such nutrients as omega-3 fatty acids, some antioxidants and vitamins, and low in saturated fatty acids (SFAs) and trans-fatty acids (TFAs) are inversely associated with low semen quality parameters. In terms of food groups, fish, shellfish and seafood, poultry, cereals, vegetables and fruits, and low-fat dairy products have been positively related to sperm quality. However, diets rich in processed meat, soy foods, potatoes, full-fat dairy products, coffee, alcohol and sugar-sweetened beverages and sweets have been inversely associated with the quality of semen in some studies. The few studies relating male nutrient or food intake and fecundability also suggest that diets rich in red meat, processed meat, tea and caffeine are associated with a lower rate of fecundability. This association is only controversial in the case of alcohol. The potential biological mechanisms linking diet with sperm function and fertility are largely unknown and require further study. Treatment Treatments vary according to the underlying disease and the degree of the impairment of the males fertility. Further, in an infertility situation, the fertility of the female needs to be considered.Pre-testicular conditions can often be addressed by medical means or interventions. Testicular-based male infertility tends to be resistant to medication. Usual approaches include using the sperm for intrauterine insemination (IUI), in vitro fertilization (IVF), or IVF with intracytoplasmatic sperm injection (ICSI). With IVF-ICSI even with a few sperm pregnancies can be achieved. Obstructive causes of post-testicular infertility can be overcome with either surgery or IVF-ICSI. Ejaculatory factors may be treatable by medication, or by IUI therapy or IVF. Vitamin E helps counter oxidative stress, which is associated with sperm DNA damage and reduced sperm motility. A hormone-antioxidant combination may improve sperm count and motility. Giving oral antioxidants to men in couples undergoing in vitro fertilisation for male factor or unexplained subfertility may lead to an increase in the live birth rate but overall the risk of adverse effects is unclear. Hormonal therapy Administration of luteinizing hormone (LH) (or human chorionic gonadotropin) and follicle-stimulating hormone (FSH) is very effective in the treatment of male infertility due to hypogonadotropic hypogonadism. Although controversial, off-label clomiphene citrate, an antiestrogen, may also be effective by elevating gonadotropin levels.Though androgens are absolutely essential for spermatogenesis and therefore male fertility, exogenous testosterone therapy has been found to be ineffective in benefiting men with low sperm count. This is thought to be because very high local levels of testosterone in the testes (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels) are required to mediate spermatogenesis, and exogenous testosterone therapy (which is administered systemically) cannot achieve these required high local concentrations (at least not without extremely supraphysiological dosages). Moreover, exogenous androgen therapy can actually impair or abolish male fertility by suppressing gonadotropin secretion from the pituitary gland, as seen in users of androgens/anabolic steroids (who often have partially or completely suppressed sperm production). This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes) and because FSH is independently critical for spermatogenesis. In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis. However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels. As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.Low-dose estrogen and testosterone combination therapy may improve sperm count and motility in some men, including in men with severe oligospermia. Research Researchers at Münster University developed in vitro culture conditions using a three-dimensional agar culture system which induces mouse testicular germ cells to reach the final stages of spermatogenesis, including spermatozoa generation. If reproduced in humans, this could potentially enable infertile men to father children with their own sperm.Researchers from Montana State University developed precursors of sperm from skin cells of infertile men.Sharpe et al. comment on the success of intracytoplasmic sperm injection (ICSI) in women saying, "[t]hus, the woman carries the treatment burden for male infertility, a fairly unique scenario in medical practice. Ironically, ICSIs success has effectively diverted attention from identifying what causes male infertility and focused research onto the female, to optimize the provision of eggs and a receptive endometrium, on which ICSIs success depends." Prevalence Currently, there are no solid numbers on how many couples worldwide experience infertility, but the World Health Organization estimates between 60 and 80 million couples are affected. The population in different regions have varying amounts of infertility. Starting in the late 20th century, scientists have expressed concerns about the declining semen quality in men. A study was done in 1992 with men who had never experienced infertility showed that the amount of sperm in semen had declined by 1% per year since 1938. Further research a few years later also confirmed the decline in sperm count and also seminal volume. Various studies in Finland, Southern Tunisia, and Argentina also showed a decline in sperm count, motility, morphology, and seminal volume. Males from India had a 30.3% decline in sperm count, 22.9% decline in sperm motility, and a 51% decrease in morphology over a span of a decade. Doctors in India disclosed that the sperm count of a fertile Indian male had decreased by a third over a span of three decades. Some factors may include exposure to high temperatures at places such as factories. A 1 degree increase in temperature will reduce 14% of spermatogenesis.Researchers in Calcutta conducted a study between 1981 and 1985 that also showed a decrease in sperm motility and seminal volume, but no change in sperm concentration. Society and culture There are a variety of social stigmas that surround male infertility throughout the world. A lot of research has pointed to the relationship between infertility and emasculation. This association has led to infertility being less studied and diagnosed in men over time. In places like Egypt, Zimbabwe, and Mexico, erectile dysfunction also known as impotence, is considered a determinant of infertility. When stereotypical ideals of manhood are virility and strength, men sharing problems of infertility can face feelings of inadequacy, unworthiness, and have thoughts of suicide. In many cases, a variety of socio-economic interventions come in play to determine penile activity. For the Shona people, since impotence is linked to infertility, an examination to check on the penile function spans from infancy to post marriage. At infancy, there are daily check-ups by the mothers on the sons erection and urine quality. When the son reaches puberty, they are asked to ejaculate in river banks and for their male elders to examine sperm quality. The traditions last until post-marriage, when the family of the bride take part to check on consummation and the grooms sperm quality. Crisis See also Female infertility Fertility preservation Fertility testing Infertility Male accessory gland infection (MAGI) Meiosis Oncofertility Paternal age effect Spermatogenesis Vasectomy References == External links ==

Circadian rhythm sleep disorder

Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in ones biological clock system, or by misalignment between ones endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD. Overview Humans, like most living organisms, have various biological rhythms. These biological clocks control processes that fluctuate daily (e.g., body temperature, alertness, hormone secretion), generating circadian rhythms. Among these physiological characteristics, the sleep-wake propensity can also be considered one of the daily rhythms regulated by the biological clock system. Humans sleeping cycles are tightly regulated by a series of circadian processes working in tandem, allowing for the experience of moments of consolidated sleep during the night and a long wakeful moment during the day. Conversely, disruptions to these processes and the communication pathways between them can lead to problems in sleeping patterns, which are collectively referred to as circadian rhythm sleep disorders. Normal rhythm A circadian rhythm is an entrainable, endogenous, biological activity that has a period of roughly twenty-four hours. This internal time-keeping mechanism is centralized in the suprachiasmatic nucleus (SCN) of humans, and allows for the internal physiological mechanisms underlying sleep and alertness to become synchronized to external environmental cues, like the light-dark cycle. The SCN also sends signals to peripheral clocks in other organs, like the liver, to control processes such as glucose metabolism. Although these rhythms will persist in constant light or dark conditions, different Zeitgebers (time givers such as the light-dark cycle) give context to the clock and allow it to entrain and regulate expression of physiological processes to adjust to the changing environment. Genes that help control light-induced entrainment include positive regulators BMAL1 and CLOCK and negative regulators PER1 and CRY. A full circadian cycle can be described as a twenty-four hour circadian day, where circadian time zero (CT 0) marks the beginning of a subjective day for an organism and CT 12 marks the start of subjective night.Humans with regular circadian function have been shown to maintain regular sleep schedules, regulate daily rhythms in hormone secretion, and sustain oscillations in core body temperature. Even in the absence of Zeitgebers, humans will continue to maintain a roughly 24-hour rhythm in these biological activities. Regarding sleep, normal circadian function allows people to maintain balance rest and wakefulness that allows people to work and maintain alertness during the days activities, and rest at night.Some misconceptions regarding circadian rhythms and sleep commonly mislabel irregular sleep as a circadian rhythm sleep disorder. In order to be diagnosed with CRSD, there must be either a misalignment between the timing of the circadian oscillator and the surrounding environment, or failure in the clock entrainment pathway. Among people with typical circadian clock function, there is variation in chronotypes, or preferred wake and sleep times, of individuals. Although chronotype varies from individual to individual, as determined by rhythmic expression of clock genes, people with typical circadian clock function will be able to entrain to environmental cues. For example, if a person wishes to shift the onset of a biological activity, like waking time, light exposure during the late subjective night or early subjective morning can help advance ones circadian cycle earlier in the day, leading to an earlier wake time. Diagnosis The International Classification of Sleep Disorders classifies Circadian Rhythm Sleep Disorder as a type of sleep dyssomnia. Although studies suggest that 3% of the adult population has a CRSD, many people are often misdiagnosed with insomnia instead of a CRSD. Of adults diagnosed with sleep disorders, an estimated 10% have a CRSD and of adolescents with sleep disorders, an estimated 16% may have a CRSD. Patients diagnosed with circadian rhythm sleep disorders typically express a pattern of disturbed sleep, whether that be excessive sleep that intrudes on working schedules and daily functions, or insomnia at desired times of sleep. Note that having a preference for extreme early or late wake times are not related to a circadian rhythm sleep disorder diagnosis. There must be distinct impairment of biological rhythms that affects the persons desired work and daily behavior. For a CRSD diagnosis, a sleep specialist gathers the history of a patients sleep and wake habits, body temperature patterns, and dim-light melatonin onset (DLMO). Gathering this data gives insight into the patients current schedule, as well as the physiological phase markers of the patients biological clock.The start of the CRSD diagnostic process is a thorough sleep history assessment. A standard questionnaire is used to record the sleep habits of the patient, including typical bedtime, sleep duration, sleep latency, and instances of waking up. The professional will further inquire about other external factors that may impact sleep. Prescription drugs that treat mood disorders like tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants are associated with abnormal sleep behaviors. Other daily habits like work schedule and timing of exercise are also recorded—because they may impact an individuals sleep and wake patterns. To measure sleep variables candidly, patients wear actigraphy watches that record sleep onset, wake time, and many other physiological variables. Patients are similarly asked to self-report their sleep habits with a week-long sleep diary to document when they go to bed, when they wake up, etc. to supplement the actigraphy data. Collecting this data allows sleep professionals to carefully document and measure patients sleep habits and confirm patterns described in their sleep history.Other additional ways to classify the nature of a patients sleep and biological clock are the morningness-eveningness questionnaire (MEQ) and the Munich ChronoType Questionnaire, both of which have fairly strong correlations with accurately reporting phase advanced or delayed sleep. Questionnaires like the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) help gauge the severity of sleep disruption. Specifically, these questionnaires can help the professional assess the patients problems with sleep latency, undesired early-morning wakefulness, and problems with falling or staying asleep.Tayside childrens sleep questionnaire is a ten-item questionnaire for sleep disorders in children aged between one and five years old. Types Currently, the International Classification of Sleep Disorders (ICSD-3) lists 6 disorders under the category of circadian rhythm sleep disorders.CRSDs can be categorized into two groups based on their underlying mechanisms: The first category is composed of disorders where the endogenous oscillator has been altered, known as intrinsic type disorders. The second category consists of disorders in which the external environment and the endogenous circadian clock are misaligned, called extrinsic type CRSDs. Intrinsic Delayed sleep phase disorder (DSPD): Individuals who have been diagnosed with delayed sleep phase disorder have sleep-wake times which are delayed when compared to normal functioning individuals. People with DSPD typically have very long periods of sleep latency when they attempt to go to sleep during conventional sleeping times. Similarly, they also have trouble waking up at conventional times. Advanced sleep phase disorder (ASPD): People with advanced sleep phase disorder exhibit characteristics opposite to those with delayed sleep phase disorder. These individuals have advanced sleep wake times, so they tend to go to bed and wake up much earlier as compared to normal individuals. ASPD is less common than DSPD, and is most prevalent within older populations.Familial Advanced Sleep Phase Syndrome (FASPS) is linked to an autosomal dominant mode of inheritance. It is associated with a missense mutation in human PER2 that replaces Serine for a Glycine at position 662 (S662G). Families that have this mutation in PER2 experience extreme phase advances in sleep, waking up around 2 AM and going to bed around 7 PM. Irregular sleep–wake rhythm disorder (ISWRD) is characterized by a normal 24-hr sleeping period. However, individuals with this disorder experience fragmented and highly disorganized sleep that can manifest in the form of waking frequently during the night and taking naps during the day, yet still maintaining sufficient total time asleep. People with ISWRD often experience a range of symptoms from insomnia to excessive daytime sleepiness. Non-24-hour sleep–wake disorder (N24SWD): Most common in individuals that are blind and unable to detect light, is characterized by chronic patterns of sleep/wake cycles which are not entrained to the 24-hr light-dark environmental cycle. As a result of this, individuals with this disorder will usually experience a gradual yet predictable delay of sleep onset and waking times. Patients with DSPD may develop this disorder if their condition is untreated. Extrinsic Shift work sleep disorder (SWSD): Approximately 9% of Americans who work night or irregular work shifts are believed to experience shift work sleep disorder. Night shift work directly opposes the environmental cues that entrain our biological clock, so this disorder arises when an individuals clock is unable to adjust to the socially imposed work schedule. Shift work sleep disorder can lead to severe cases of insomnia as well as excessive daytime sleepiness. Jet lag: Jet lag is best characterized by difficulty falling asleep or staying asleep as a result of misalignment between ones internal circadian system and external, or environmental cues. It is typically associated with rapid travel across multiple time zones. Alzheimers disease CRSD has been frequently associated with excessive daytime sleepiness and nighttime insomnia in patients diagnosed with Alzheimers disease (AD), representing a common characteristic among AD patients as well as a risk factor of progressive functional impairments. On one hand, it has been stated that people with AD have melatonin alteration and high irregularity in their circadian rhythm that lead to a disrupted sleep-wake cycle, probably due to damage on hypothalamic SCN regions typically observed in AD. On the other hand, disturbed sleep and wakefulness states have been related to worsening of an AD patients cognitive abilities, emotional state and quality of life. Moreover, the abnormal behavioural symptoms of the disease negatively contribute to overwhelming patients relatives and caregivers as well.However, the impact of sleep-wake disturbances on the subjective experience of a person with AD is not yet fully understood. Therefore, further studies exploring this field have been highly recommended, mainly considering the increasing life expectancy and significance of neurodegenerative diseases in clinical practices. Treatment Possible treatments for circadian rhythm sleep disorders include: Chronotherapy, best shown to effectively treat delayed sleep phase disorder, acts by systematically delaying an individuals bedtime until their sleep-wake times coincide with the conventional 24-hr day. Light therapy utilizes bright light exposure to induce phase advances and delays in sleep and wake times. This therapy requires 30–60 minutes of exposure to a bright (5,000–10,000 lux) white, blue, or natural light at a set time until the circadian clock is aligned with the desired schedule. Treatment is initially administered either upon awakening or before sleeping, and if successful may be continued indefinitely or performed less frequently. Though proven very effective in the treatment of individuals with DSPD and ASPD, the benefits of light therapy on N24SWD, shift work disorder, and jet lag have not been studied as extensively. Hypnotics have also been used clinically alongside bright light exposure therapy and pharmacotherapy for the treatment of CRSDs such as Advanced Sleep Phase Disorder. Additionally, in conjunction with cognitive behavioral therapy, short-acting hypnotics also present an avenue for treating co-morbid insomnia in patients with circadian sleep disorders. Melatonin, a naturally occurring biological hormone with circadian rhythmicity, has been shown to promote sleep and entrainment to external cues when administered in drug form (0.5–5.0 mg). Melatonin administered in the evening causes phase advances in sleep-wake times while maintaining duration and quality of sleep. Similarly, when administered in the early morning, melatonin can cause phase delays. It has been shown most effective in cases of shift work sleep disorder and delayed phase sleep disorder, but has not been proven particularly useful in cases of jet lag. Dark therapy, for example, the use of blue-blocking goggles, is used to block blue and blue-green wavelength light from reaching the eye during evening hours so as not to hinder melatonin production. See also References External links Circadian Sleep Disorders Network An American Academy of Sleep Medicine Review: Circadian Rhythm Sleep Disorders: Part I, Basic Principles, Shift Work and Jet Lag Disorders. PDF, 24 pages. November 2007. An American Academy of Sleep Medicine Review: Circadian Rhythm Sleep Disorders: Part II, Advanced Sleep Phase Disorder, Delayed Sleep Phase Disorder, Free-Running Disorder, and Irregular Sleep–Wake Rhythm. PDF, 18 pages. November 2007. An American Academy of Sleep Medicine Report: Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders, November 1, 2007 NASA Sleep–Wake Actigraphy and Light Exposure During Spaceflight-Long Experiment

Hypothalamic disease

Hypothalamic disease is a disorder presenting primarily in the hypothalamus, which may be caused by damage resulting from malnutrition, including anorexia and bulimia eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury to the hypothalamus. The hypothalamus is the control center for several endocrine functions. Endocrine systems controlled by the hypothalamus are regulated by antidiuretic hormone (ADH), corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, oxytocin, all of which are secreted by the hypothalamus. Damage to the hypothalamus may impact any of these hormones and the related endocrine systems. Many of these hypothalamic hormones act on the pituitary gland. Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland.Numerous dysfunctions manifest as a result of hypothalamic disease. Damage to the hypothalamus may cause disruptions in body temperature regulation, growth, weight, sodium and water balance, milk production, emotions, and sleep cycles. Hypopituitarism, neurogenic diabetes insipidus, tertiary hypothyroidism, and developmental disorders are examples of precipitating conditions caused by hypothalamic disease. Hypopituitarism The hypothalamus and pituitary gland are tightly integrated. Damage to the hypothalamus will impact the responsiveness and normal functioning of the pituitary. Hypothalamic disease may cause insufficient or inhibited signalling to the pituitary leading to deficiencies of one or more of the following hormones: thyroid-stimulating hormone, adrenocorticotropic hormone, beta-endorphin, luteinizing hormone, follicle-stimulating hormone, and melanocyte–stimulating hormones. Treatment for hypopituitarism involves hormone replacement therapy. Neurogenic diabetes insipidus Neurogenic diabetes insipidus may occur due to low levels of ADH production from the hypothalamus. Insufficient levels of ADH result in increased thirst and urine output, and prolonged excessive urine excretion increases the risk of dehydration. Tertiary hypothyroidism The thyroid gland is an auxiliary organ to the hypothalamus-pituitary system. Thyrotropin-releasing hormone (TRH) produced by the hypothalamus signals to the pituitary to release thyroid-stimulating hormone (TSH), which then stimulates the thyroid to secrete T4 and T3 thyroid hormones. Secondary hypothyroidism occurs when TSH secretion from the pituitary is impaired, whereas tertiary hypothyroidism is the deficiency or inhibition of TRH.Thyroid hormones are responsible for metabolic activity. Insufficient production of the thyroid hormones result in suppressed metabolic activity and weight gain. Hypothalamic disease may therefore have implications for obesity. Developmental disorders Growth hormone-releasing hormone (GHRH) is another releasing factor secreted by the hypothalamus. GHRH stimulates the pituitary gland to secrete growth hormone (GH), which has various effects on body growth and sexual development. Insufficient GH production may cause poor somatic growth, precocious puberty or gonadotropin deficiency, failure to initiate or complete puberty, and is often associated with rapid weight gain, low T4, and low levels of sex hormones. Sleep disorders Non-24-hour sleep-wake syndrome, a disabling condition in which ones sleep/wake cycle is longer, or rarely, shorter, than the standard 24 hours, is thought to involve or be caused by, at least in some cases, an abnormal functioning of the suprachiasmatic nucleus (SCN) in the hypothalamus. References == External links ==

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma (particularly marginal zone lymphomas) or, in rare cases termed Richters transformation, chronic lymphocytic leukemia. An underlying immunodeficiency is a significant risk factor for development of the disease. Infections with the Epstein–Barr virus (EBV), Kaposis sarcoma-associated herpesvirus, human immunodeficiency virus (i.e. HIV), and the Helicobacter pylori bacterium are also associated with the development of certain subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained step-wise acquisition of increasing numbers of gene mutations and changes in gene expression that occur in, and progressively promote the malignant behavior of, certain B-cell types.Diagnosis of DLBCL is made by removing a portion of the tumor through a biopsy, and then examining this tissue using a microscope. Usually a hematopathologist makes this diagnosis. Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses, and recommended treatments. However, the usual treatment for most subtypes of DLBCL is chemotherapy combined with a monoclonal antibody drug that targets the diseases cancerous B-cells, usually rituximab. Through these treatments, more than half of all patients with DLBCL can be cured; the overall cure rate for older adults is less than this but their five-year survival rate has been around 58%. Subtypes of diffuse large B-cell lymphoma Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes, many of which are difficult to separate from one another based on well-defined and widely accepted criteria. The World Health Organization, 2008, classification system defined more than a dozen subtypes, each of which was identified based on the location of the tumor, the presence of other cell types such as T cells in the tumor, and whether the patient had certain other illnesses related to DLBCL. Based on further research, the World Health Organization, 2016, reclassified DLBCL into its most common subtype, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). DLBCL, NOS represents 80–85% of all DLBCL. The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology, (i.e. microscopic appearance), immunophenotype, (i.e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses. Some cases of DLBCL, NOS, while not included in the 2016 World Health Organizations classification, are clearly associated with, and caused by, chronic infection by the bacterium, Helicobacter pylori. Diffuse large B-cell lymphoma, not otherwise specified DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype, and/or pathogen-associated criteria of other DLBCL subtypes are termed Diffuse large B-cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases, is a diagnosis of exclusion. In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment. Presenting signs and symptoms About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases, the most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach, or, less commonly, in other sites such as the testicles, breasts, uterus, ovaries, kidneys, adrenal glands, thyroid gland, or bone. The presenting signs and symptoms in these cases reflect the presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction. Individuals with nodal or extranodal disease also present with: systemic B symptoms such as weight loss, night sweats, fevers, and/or fatigue in ~33% of cases; unexplained elevations in their blood levels of lactic acid dehydrogenase and beta-2 microglobulin in many cases; malignant cells infiltrating their bone marrow in 10–20% of cases; and/or localized Stage I or II disease in up to 50% of cases and disseminated Stage III or IV disease in the remaining cases. Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis. Uncommonly, DLBCL may arise as a transformation of marginal zone lymphoma (MZL) in individuals who have been diagnosed with this indolent cancer 4–5 years (median times) previously. Prognostic indicators based on clinical presentation The International Prognostic Index and more recently, the Indexs age-adjusted variant use age >60 years, elevated serum lactate dehydrogenase levels, low performance status, and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS. In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the central nervous system while disease initially involving the kidneys, adrenal glands, ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses. Pathophysiology Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of gene changes such as mutations, altered expressions, amplifications (i.e. increases in the number of copies of specific genes), and tranlocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate the maturation, proliferation, survival, spread, evasion of the immune system, and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this diseases development and/or progression. BCL2: This gene is a protooncogene, i.e. a normal gene that can become cancer-causing when mutated or overexpressed. Its product, Bcl-2 protein, regulates cellular apoptosis (i.e. survival) by inhibiting the apoptosis-causing proteins, Bcl-2-associated X protein and Bcl-2 homologous antagonist killer. BCL6: This genes product, Bcl-6, is a repressor of transcription that regulates the expression of other genes which control cell maturation, proliferation, and survival. MYC: This protooncogenes product, Myc, encodes a transcription factor which regulates the expression of other genes whose products stimulate cell proliferation and expansion to extra-nodal tissues. EZH2: This genes product, the EZH2 protein, is a histone-lysine N-methyltransferase. It thereby regulates the expression of other genes which control lymphocyte maturation. MYD88: This genes product is a signal transducing adaptor protein essential for the transduction of interleukin-1 and toll-like receptor signaling pathways. It thereby regulates NF-κB and MAPK/ERK signaling pathways that control cell proliferation and survival. CREBBP: This genes product is a transcriptional coactivator; it activates numerous transcription factors, some of which control cell proliferation. CD79A and CD79B: these genes products are critical components of the B-cell receptor. Mutations in either gene can cause uncontrolled cell activation and proliferation. PAX5: this genes product, Pax-5, is a transcription factor that controls the development, maturation, and survival of B-cells; it also controls expression of the MYC gene in these cells.As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, PI3K/AKT/mTOR, JAK-STAT0, MAPK/ERK, B-cell receptor, toll-like receptor, and NF-κB signaling pathways and thereby uncontrolled pro-malignant behaviors. Diagnosis Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins (e.g. CD20, CD19, CD22, CD79, PAX5, BOB1, OCT2, an immunoglobulin [usually IgM but occasionally IgG or IgA)], CD30, and in ~20–25% of cases PD-L1 or PD-L2 (PD-L1 and PD-L2 are transmembrane proteins that normally function to suppress attack by the immune system). These cells arrange in a diffuse pattern, efface the tissues architecture, and resemble Centroblast cells (80% of cases), Immunoblast cells (8–10% of cases), or anaplastic cells (9% of cases; anaplastic cells have bizarre nuclei and other features that may mimic the Reed–Sternberg cells of Hodgkin disease or the neoplastic cells of anaplastic large cell lymphoma). Rarely, these neoplastic cells are characterized as having signet ring or spindle shaped nuclei, prominent cytoplasmic granules, multiple microvillus projections, or, when viewed by electron microscopy, tight junctions with other cells. These neoplastic tissue infiltrates are often accompanied by small non-malignant T-cell lymphocytes and histiocytes that have a reactive morphology. Variants of DLBCL, NOS The World Health Organization, 2016, requires that the neoplastic cells in DLBCL, NOS be further defined based on whether they are derived from germinal center B-cells (i.e. GBC) or activated B-cells (i.e. ABC) as identified by gene expression profiling (GEP) or are GBC or non-GBC as identified by immunohistochemical (IHC) analyses. As identified by GEP, which measures all cellular messenger RNAs, GBC and ABC represent about 50 and ~35% of DLBCL, NOS cases, respectively, with ~15% of cases being unclassifiable. IHC analyses measure the cellular expression of specific proteins using a panel of fluorescent antibodies that bind to and therefore stain a set of key proteins. For example, one commercially available panel uses three antibodies to detect CD10, BCL6, and MUM1 proteins; GBC express whereas ABC and unidentified cells do not express these proteins; accordingly, this as well as other IHC panels classify ABC and undetermined neoplastic cell types together as non-GBC. Individuals with the ABC, unclassifiable, and non-GBC variants have significantly worse prognoses than individuals with the GBC variant: respective 5 year progression-free and overall survival rates have been reported to be 73–80% for GBC variants and 31–56% for ABC variants. Clinically, however, most DLBCL, NOS cases are analyzed by IHC and therefore classified as either GBC or non-GBC variants with non-GBC variants having progression-free and overall survival rates similar to those of the ABC variants.Gene and protein markers in the neoplastic cells of DLBCL, NOS that have clinical significance include CD5, MYC, BCL2, BCL6, CD20, CD19, CD22, CD30, PD-L1, and PD-L2. The 5–10% of DLBCL, NOS cases in which the neoplastic cells express CD5 have a very poor prognosis that is not improved by even aggressive treatment regimens. Cases in which fluorescence in situ hybridization analysis show that the neoplastic cells in this disease bear translocations in both the MYC and BCL2 genes or MYC and BCL6 genes (termed double hit lymphomas) or in all three genes (termed triple hit lymphomas) are associated with advanced disease that spreads to the central nervous system. These lymphomas, termed high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements or, more simply, DH/THL, are regarded as borderline DLBCL,NOS. They represent 6–14% of all DLBCL, NOS and have had long-term survival rates of only 20–25%. Another variant B-cell lymphoma that is also considered to be a borderline DLBCL, NOS is termed high-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS). These two aggressive borderline B-cell lymphomas were previously grouped together as "B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma" (i.e. BCLU) but were separated into DH/THL and HGBC, NOS by the World Health Organization, 2016. The neoplastic cells in a related variant, double expresser lymphoma (i.e. DEL), express the products of MYC and BCL2 genes, i.e. c-Myc and bcl-2 proteins, respectively, but do not have translocations in either of their genes. DEL, which represents about one-third of all DLBCL, NOS cases, has a poorer prognosis than standard DLBCL, NOS but not as poor as DH/THL cases. Cases in which the neoplastic cells have alterations in the MYC gene or its expression without changes in BLC2 or BLC6 also have a poor prognosis, particularly in cases where the MYC gene translocates (i.e. rearranges) with one of the immunoglobulin gene loci. DLBCL that begin in the testicles are a variant of DLBCL, NOS that some authors suggest should be classified as a distinct DLBCL subtype. This variant, termed Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), is a DLBCL, NOS that in >75% of cases involves activated B-cells, i.e. ABC. These cells, which typically have a centroblast-like morphology, infiltrate one or, in ~6% of cases, both testicles. PT-DLBCL is an aggressive disease that often spreads to the central nervous system and has median overall survival and progression-free survival times of 96 and 49 months, respectively.The neoplastic cells in almost all cases of DLBCL, NOS express CD20. Commercially available anti-CD20 antibody agents such as rituximab or Obinutuzumab (which is sometimes used in place of rituximab) kill cells that express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts adaptive immune system. The addition of one of these immunotherapy agents to chemotherapy protocols has greatly improved the prognosis of most DLBCL, NOS variants. Neoplastic cell expression of CD30, found in 10–15% of DLBCL, NOS cases is a favorable prognostic indicator. As indicated in the following Treatments and prognoses section, expression of the CD20 and CD30 proteins as well as the CD19, CD20 CD22, CD30, CD79A, CD79B, and D-L1 proteins, expression of the MYC, BCL2, MYD88nd, and CREBBP genes, and expression of the PI3K/AKT/mTOR, JAK-STAT, B-cell receptor, toll-like receptor, and NF-κB signaling pathways are being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC DLBCL, NOS cases. Treatments and prognoses First-line therapy First-line therapy for patients with the GBC variant of DLBCL, NOS is R-CHOP. R-CHOP consists of rituximab, three chemotherapy drugs (cyclophosphamide, doxorubicin, and vincristine) and a glucocorticoid (either prednisone or prednisolone). The regimen achieves cure, relapse following remission, and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in GBC variant cases. Relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R-CHOP have poorer prognoses. R-CHOP is less effective and not recommended for patients who have MYC, BL2, and/or BL6 rearrangements regardless of their GBC, ABC, or non-GBC type. One recommendation for treating these DH/THL cases is the DA-R-EPOCH regimen (dose-adjusted rituximab, etoposide, prednisolone, oncovin, cyclophosphamide, and hydroxydaunorubicin). S-R-EPOCH achieves 2 year survival rates of 40–67% compared to a ~25% survival rate for R-CHOP in these cases. DA-R-EPOCH has also been recommended for patients with double expresser lymphoma although some experts recommend treating this variant more like a typical DLCBL, NOS. First-line therapy for patients with the ABC, undetermined, or non-GBC variants has been the DA-R-EPOCH regimen. Patients with these variants (including those with double expresser lymphoma) have had a ~40% cure rate when treated with it. A randomized clinical trial conducted in France reported that a R-ACVBP chemotherapy regimen (rituximab, adriamycin, cyclophosphamide, vindesine, bleomycin, and cytarabine followed by sequential consolidation therapy with systemic methotrexate, ifosfamide, and etoposide, and then cytarabine) achieved significantly better response rates than R-CHOP in ABC/NGC variant cases lymphoma. In DLBCL, NOS variants which trend to spread or to the central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as prophylaxis to reduce the incidence of this complication. The role of Autologous stem-cell transplantation as an addition to first-line therapy in the treatment of DLBCL, NOS, including cases with a poor prognosis, is unclear.A phase I clinical research trial found that the addition of lenalidomide to the R-CHOP regimen produce an ~80% complete response rate in GBC as well as non- GBC DLBCL, NOS variants. Two phase III clinical research trials are underway to confirm these results and determine if the R-CHOP + lenalidomide regimen is superior to R-CHOP in the up-front treatment of GBC and/or non-GBC variants. Treatment of recurrent and refractory DLBCL, NOS Patients with DLBCL, NOS who relapse or progress following first-line therapy have been treated with "salvage regimens" consisting of high-dose (also termed high-intensity) chemotherapy conditioning drugs followed by autologous stem cell transplantation. This regimen has attained 3-year progression-free survival rates of 21–37%. Relapse following this treatment carries a very poor prognosis with median overall survival times of ~10 months. Patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by allogeneic stem cell transplantation. This regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively. Further studies are underway to determine the best treatment regimens for these cases. Patients refractory to first-line therapy or who relapse within 12 months of receiving salvage therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively. The prognosis of these patients appears to be improved by using CAR-T therapy. Chimeric antigen receptor T cell (i.e. CAR-T) adoptive cellular immunotherapy has emerged as a recent advance in treating refractory and relapsed DLBCL, NOS (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel). Chimeric antigen receptor T cells are genetically engineered to express: 1) an artificial T-cell receptor consisting of antigen-recognition and attached hinge domains expressed on their surface membranes; 2) a surface membrane-spanning domain; 3) an intracellular domain which, when the antigen-recognition domain binds its targeted antigen, activates signaling pathways that cause the T-cell to attack and kill cells that bear the recognized antigen on their surface membranes; and 4), in more recently devised second generation CAR-T strategies, an associated intracellular co-stimulating molecule (e.g. CD28 or 4-1BB) which augments activation of the cell-killing signaling pathways. CAR-T therapy, as it pertains to DLBCL, NOS, kills a patients neoplastic B-cells by isolating this patients T-cells; genetically engineering these cells to express an artificial T-cell receptor designed to bind an antigen expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been CD19, a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS. However, design of CARs as well as the antigens chosen to be their targets are constantly being changed in order to improve the efficacy of this therapeutic strategy. CAR-T therapy for DLBCL, NOS has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. Patients are treated first with a conditioning chemotherapy regimen, usually cyclophosphamide and fludarabine, and then infused with their own T-cells that have been engineered to attack CD19-bearing or, rarely, CD20-bearing cells. A meta-analysis of 17 studies using this or very similar approaches to treat DLBCL, NOS found the treatments gave complete and partial responses rates of 61% and 43%, respectively. While these studies did not have control groups and were too recent for meaningful estimates of remission durations, the remission rates were higher than expected using other treatment approaches. Significant and potentially lethal therapeutic complications of this therapy included development of the cytokine release syndrome (21% of cases), neurotoxicity, i.e. the CAR-T cell-related encephalopathy syndrome (9% of cases), and the hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (i.e. a form of Hemophagocytic lymphohistiocytosis). Individual studies within and outside of this meta-analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and neurotoxicity responses to this therapy. As a consequence of these studies, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use of the European Medicines Agency recommend granting marketing authorization for tisagenlecleucel (i.e. chimeric antigen receptor T cells directed against CD19) in adult patients with DLBCL, NOS who have relapsed after or are refractory to two or more lines of systemic therapy. The Committee for Orphan Medicinal Products of the European Medicines Agency recommends tisagenlecleucel retain its orphan drug designation. The USA Food and Drug Administration (FDA) has also approved the use of this drug for relapsed or refractory DLBCL of the large B-cell lymphoma subtype in patients who have failed after two or more lines of systemic therapy. Monoclonal antibodies directed against CD19, CD22, CD30, and PD-L1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in DLBCL, NOS. In August 2020, the FDA approved the humanized Fc-modified cytolytic CD19 targeting monoclonal antibody tafasitamab in combination with lenalidomide as a treatment for adult patients with relapsed or refractory DLBCL. In April 2021, the FDA approved the CD19-directed antibody-drug conjugate loncastuximab tesirine as a treatment for adult patients with relapsed or refractory DLBCL after systemic therapy. Emerging therapies Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, brentuximab vedotin may be a useful addition to chemotherapy treatment protocols. This agent is a CD30-targeting antibody that delivers a toxin, monomethyl auristatin E, to CD30-expressing cells, has therapeutic efficacy against other CD30-expressing lymphomas, and may prove useful in treating the 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the EZH2, BCL2 and CREBBP genes and overactive PI3K/AKT/mTOR and JAK-STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the MYD88, CD79A and CD79B (polatuzumab vedotin) genes and overactive B-cell receptor, toll-like receptor, and NF-κB signaling pathways. These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC cases. CUDC-907, an inhibitor of PI3K and histone deacetylases, is being evaluated in two separate clinical trials for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene. GSK525762, an inhibitor of the BET family of proteins, suppresses expression of the MYC gene and is undergoing a phase I clinical trial for the treatment of high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements (i.e. DH/THL). RO6870810, another BET inhibitor, in combination with Venetoclax, an inhibitor of the Bcl-2 protein, is likewise in a phase I clinical trial for the treatment of DH/THL. Pharmacological inhibition of BCL-2 is effective in most B cell lymphomas, but often leads to acquired resistance due to the expression of other major anti-apoptotic BCL-2 family proteins like BCL-XL and MCL-1. Combined therapy using MCL-1 inhibitor (S63845) or BCL-XL inhibitor (A

Diffuse large B-cell lymphoma

-1331852) in addition to Venetoclax can be a solution to overcome this issue. Subtypes of diffuse large B-cell lymphoma DLBCL subtypes have been sorted into groups based on their distinctive morphology or immunophenotype, distinctive clinical issues, and distinctive virus-driven etiology. The prognoses and treatment of these subtypes varies with their severity. Most subtypes are aggressive diseases and consequently treated in a manner similar to DLBCL,NOS. Further details on these subtypes, including their treatments, can be found in their respective main article linkages. DLBCL with a distinctive morphology or immunophenotype T cell/histiocyte-rich large B-cell lymphoma T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a DLBCL in which tumors containing small numbers of usually large neoplastic B-cells embedded in a background of reactive T-cells and histiocytes develop in the liver, spleen, bone marrow and/or, rarely other sites. Patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%. ALK+ large B-cell lymphoma ALK+ large B-cell lymphoma (ALK+ LBCL) is a DLBCL in which neoplastic lymphocytes that express the ALK tyrosine kinase receptor protein infiltrate lymph nodes as well as extranodal sites, e.g. the mediastinum, bones, bone marrow, nasopharynx, tongue, stomach, liver, spleen, and skin. About 60% of these individuals present with advanced disease. ALK+ LBCL has an overall 5 year survival rate of ~34%. Plasmablastic lymphoma Plasmablastic lymphoma (PBL) is a DLBCL in which neoplastic immunoblastic or plasmablastic cells embedded in a background of other cell types infiltrate the oral/nasal cavity or much less often the gastrointestinal tract. Some 70% of individuals with PBL are infected with EBV and/or (particularly those with oral/nasal cavity disease) human immunodeficiency virus (HIV). PBL is an aggressive disease with a median survival time of ~15 months. Intravascular large B-cell lymphoma Intravascular large B-cell lymphoma (IVLBCL) is a DLBCL in which medium- to large-sized neoplastic B-cells infiltrate small- to medium-sized blood vessels and sinusoids in the liver, spleen, and/or bone marrow. IVLBCL may be associated with the hemophagic syndrome (i.e. excessive cytokine secretion and systemic inflammation). Patients with the latter syndrome have very short survival times. The poor prognosis of this disease has been significantly improved by rituximab or similar immunochemotherapy drugs but significant proportions of these responding cases relapse, often with central nervous system involvement. Large B-cell lymphoma with IRF4 rearrangement Large B-cell lymphoma with IRF4 rearrangement (LBCL with IRF4 rearrangement) is a DLBCL in which tissue infiltrates containing intermediate- or large-sized neoplastic B-cells strongly express a chromosomal translocation involving the IRF4 gene on the short arm of chromosome 6. These cells form follicular, follicular and diffuse, or entirely diffuse infiltrates in Waldeyers tonsillar ring or other regions of the head and neck. The disease, which represents ~0.05% of all DLBCL, occurs primarily in children and young adults and typically has a good prognoses. Cases with a follicular pattern of tissue infiltrates often have indolent disease and an excellent prognosis following excision and may not need chemotherapy. Cases with a purely diffuse tissue infiltrate pattern, in contrast, often do require chemotherapy. DLBCL with distinctive clinical issues Primary mediastinal large B-cell lymphoma Primary mediastinal large B-cell lymphoma (PMBL), also termed primary mediastinal (thymic) large B-cell lymphoma, is a DLBCL in which neoplastic B-cells infiltrates are commonly located in sclerotic/fibrous tissues of the thymus and mediastinal lymph nodes. The disease represents 6–10% of all DLBCL cases, presents with early stage disease in ~80% of cases, and has an overall survival rate at 5 years of 75–85%. Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a DLBCL in which diffuse patterns of immunoblastic and/or centroblastic B-cells infiltrate the dermis and/or subcutaneous tissue principally, but not exclusively, of the legs. This diseases 5-year overall survival rate is 50–60%. Primary diffuse large B-cell lymphoma of the central nervous system Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS, also termed primary central nervous system lymphoma [PCNSL]) is a DLBCL in which diffuse patterns of neoplastic B-cells with centroblastic, immunoblastic, or poorly differentiated features infiltrate the brain, spinal cord, leptomeninges, or eye. The disease usually presents as a single lesion with a predilection for the supratentorial region of the brain but may involve the eye in 15–25% of cases, the cerebrospinal fluid in 7–42% of cases, and the spinal cord in ~1% of cases. The disease has a 5-year overall survival rate of ~30%. Diffuse large B-cell lymphoma associated with chronic inflammation Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is an Epstein–Barr virus-associated lymphoproliferative disease arising in persons with a long and persistent history of chronic inflammation. The diseases lesions consist of large, mature-appearing B-cells infiltrating the lungs pleura and nearby tissues. Most cases have occurred in patients who were given a pneumothorax (i.e. therapeutic introduction of air into the chest cavity in order to collapse and thereby "rest" the lung) to treat pulmonary tuberculosis that had progressed to a pyothorax (i.e. pus in the pleural cavity). Fibrin-associated large B-cell lymphoma (FA-DLBCL), often considered a sub-type of DLBCL-CI, is an infiltration of large neoplastic B-cells and fibrin affix to a prosthesis (e.g., cardiac valve, orthopaedic device) or accumulate within a hydrocele, pseudocyst, cardiac myxoma, or chronic subdural hematoma. The B-cells in these lesions are often but not always infected with the Epstein–Barr virus. DLBCL-CI occurring in cases of pleural empyema (sometimes termed pyothorax-associated lymphoma, i.e. PAL) is an aggressive lymphoma with a five-year overall survival rate of 20–35%; FA-DLBCL, when involving the heart (e.g. occurring on myxommas or prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), may involve life-threatening cardiovascular complications, particularly strokes. Outside of these complications, however, DLBCL-CI usually has a highly favorable outcome. Lymphomatoid granulomatosis Lymphomatoid granulomatosis (LYG) is a DLBCL in which large, atypical B-cells with immunoblastic or Hodgkin disease-like features that are infected by the Epstein-Barr virus center around and destroy the microvasculature. Lymphomatoid granulomatosis almost always involves the lung but may concurrently involve the brain, peripheral nervous system, skin, kidneys, liver, gastrointestinal tract, and/or upper respiratory tract; LYG has an increased incidence in persons with Wiskott–Aldrich syndrome or HIV or who are immunosuppression due to chemotherapy or organ transplantation. The diseases prognosis is highly variable: patients with low grade disease often require no therapy except watchful waiting while patients with high grade disease usually require chemotherapy. Primary effusion lymphoma Primary effusion lymphoma (PEL) is a DLBCL in which neoplastic B cells that resemble immunoblasts, plasmablasts, or Reed–Sternberg cells infiltrate the pleural, pericardial, or peritoneal membranes that surround the lungs, heart, and abdominal organs, respectively. This infiltration leads to the seeping of fluid into the cavities which are encased by these membranes, i.e. it leads to pleural effusions, pericardial effusions, and abdominal ascites. Some cases of PEL also involve the gastrointestinal tract and lymph nodes. The disease occurs primarily in people who are immunosuppressed or test positive for HIV and are also latently infected with Kaposis sarcoma-associated herpesvirus; PEL is an aggressive disease with an overall 1 year survival rate of ~30%. DLBCL driven by viruses Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) is a B-cell lymphoma in which neoplastic B-cells that are infected with the Epstein-Barr virus cause a disease that does not fit into other subtypes of DLBCL. In EBV+ DLBCL, small neoplastic B-cells, other lymphocyte typess, plasma cells, histiocytes and epithelioid cells interspersed with Reed–Sternberg-like cells infiltrate, almost exclusively, lymph nodes. Elderly patients with the disease have median survival times of ~2 years while young patients have long-term treatment-related remissions in >80% of cases. HHV8-positive diffuse large B-cell lymphoma, NOS HHV8-positive diffuse large B-cell lymphoma, NOS (HHV8+ DLBCL, NOS; also termed HHV8-positive diffuse large B-cell lymphoma [HHV8+ DLBCL]) is a DLBCL in which Kaposis sarcoma-associated herpesvirus-infected, medium- to large-size neoplastic B-cells that resemble lymphocytes or immunoblasts infiltrate lymph nodes (~80% of cases) and, when disseminated (20% of cases), the liver and spleen. This infiltration usually disrupts the normal architecture of the involved tissues. HHV8+ DLBCL develops in HIV-infected individuals in ~50% of cases, in individuals with multicentric Castleman disease, plasma cell variant in uncommon cases, and in individuals with Kaposi sarcoma in rare cases. HHV8+ DLBCL commonly takes an aggressive course and has a poor prognosis. Related disorders Helicobactor pylori associated diffuse large B-cell lymphoma Rare cases of DLBCL are associated with the presence of the bacterium, Helicobacter pylori, in the neoplastic B-cells. While the histology of Helicobactor pylori-associated diffuse large B-cell lymphoma (H. pylori+ DLBCL) is typical of DLBCL, the disease is sometimes a progression of mantle cell lymphoma, is often restricted to the stomach, is less aggressive that most DLBCL cases, and may respond to a drug regimen consisting of antibiotics and proton pump inhibitors directed at killing the bacterium. Perhaps because of these features of the disease, H. pylori+ DLBCL has not been classified as a DLBCL by the World Health Organization, 2016.Recent studies suggest that localized, early-stage H. pylori+ DLBCL, when limited to the stomach, is successfully treated with H. pylori eradication protocols consisting of two or more antibiotics plus a proton pump inhibitor. However, these studies also agree that patients treated with one of these H. pylori eradication regimes need to be carefully followed: those unresponsive to, or worsening on, these regimens should be switched to a chemotherapy regimen (e.g. R-CHOP) and/or, for complicated bulky disease, surgery and/or local radiotherapy. Epstein–Barr virus-positive mucocutaneous ulcer Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in which Epstein–Barr virus-infected B-cells proliferate and cause ulcerations in the mucous membranes and skin of immunosuppressed individuals. Its lesions consist of Epstein–Barr virus-positive, variable-sized, atypical B-cells that by conventional histopathologic criteria indicate the lesions are a form of DLBCL. Since these lesions regress spontaneously without anti-cancer treatment, EBVMCU is now considered a pseudo-malignant disorder. Elderly individuals that evidence the disease but have no other cause for immunosuppression may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously. Persistent and/or severely symptomatic cases have had excellent responses to rituximab. Individuals developing these ulcers as a consequence of immunosuppressive therapy generally have a remission after the dosage of the drugs used in their immunosuppressive treatments are reduced. Most of these patients do not relapse. See also Germinal center B-cell like diffuse large B-cell lymphoma References Sources Swerdlow SH, Campo E, Jaffe ES, Pileri SA, eds. (2008). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC. ISBN 978-92-832-2431-0. Goldman L, Schafer AI (2012). Goldmans Cecil Medicine (24th ed.). ISBN 978-1-4377-1604-7. Turgeon ML (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 978-0-7817-5007-3. == External links ==

Delta-beta thalassemia

Delta-beta thalassemia is a rare form of thalassemia in which there is a reduced production of hemoglobin subunit delta and hemoglobin subunit beta and raised levels of hemoglobin subunit gamma. It is an autosomal recessive disorder. Signs and symptoms An individual with delta-beta thalassemia is usually asymptomatic, however microcytosis can occur where the red blood cells are abnormally small. Mechanism Delta-beta thalassemia is autosomal recessive disorder, which means both parents are affected and two copies of the gene must be present. A carrier gets a normal gene to produce hemoglobin A, from one parent and the other parent supplies a gene which makes no hemoglobin A. Delta-beta thalassemia is considered rare.Delta-beta-thalassemia is caused by deletions of the entire delta and beta genes sequences and only gamma-globin and HbF are formed. Rarely, non-deletional forms have been reported.When two delta0 mutations are inherited, no hemoglobin A2 (alpha2, delta2) are formed. This is innocuous because only 2-3% of normal adult hemoglobin is hemoglobin A2. The individual will have normal hematological parameters (erythrocyte count, total hemoglobin, mean corpuscular volume). The delta-beta thalassemia demonstrates one mutation is at the +69 position. Relation to beta thalassemia Delta-beta thalassemia can mask the diagnosis of beta thalassemia trait. In beta thalassemia, an increase in hemoglobin A2 results, but the co-existence of a delta-beta thalassemia mutation will decrease the value of the hemoglobin A2 into the normal range, thereby obscuring the diagnosis of beta thalassemia trait Diagnosis Following the detection of hypochromic microcytic red blood cells, delta-beta thalassemia is confirmed by high-performance liquid chromatography. Treatment When needed, treatment for anemia, such as blood transfusions are used.Stem cell transplant is another option, but the donor and the individual who will receive the bone marrow transplant must be compatible, the risks involved should be evaluated. See also Alpha thalassemia Beta-thalassemia Hemoglobinopathy References Further reading Verma, S; Bhargava, M; Mittal, SK; Gupta, R (1 January 2013). "Homozygous delta-beta Thalassemia in a Child: a Rare Cause of Elevated Fetal Hemoglobin". Iranian Journal of Pediatric Hematology and Oncology. 3 (1): 222–227. ISSN 2008-8892. PMC 3915439. PMID 24575268. Kumar, B. Vinodh; Choccalingam, Chidambharam; Samuel, Premila (1 March 2016). "Incidental Identification of Possible Delta-Beta Thalassemia Trait in a Family: A Rare Cause of Elevated Hb F." Journal of Clinical and Diagnostic Research. 10 (3): BD01–BD02. doi:10.7860/JCDR/2016/16352.7409. ISSN 2249-782X. PMC 4843246. PMID 27134860. "Public Health Information Network Vocabulary Access and Distribution System (PHIN VADS)". CDC. Centers for Disease Control. Retrieved 17 September 2016. == External links ==

Varus deformity

A varus deformity is an excessive inward angulation (medial angulation, that is, towards the bodys midline) of the distal segment of a bone or joint. The opposite of varus is called valgus. EX: Varus deformity results in a decreased Q angle of the knee joint. The terms varus and valgus always refer to the direction that the distal segment of the joint points. For example, in a valgus deformity of the knee, the distal part of the leg below the knee is deviated outward, in relation to the femur, resulting in a knock-kneed appearance. Conversely, a varus deformity at the knee results in a bowlegged with the distal part of the leg deviated inward, in relation to the femur. However, in relation to the mid-line of the body, the knee joint is deviated towards the mid-line. EX: Valgus deformity results in an increased Q angle of the knee joint. Terminology The terminology is made confusing by the etymology of these words. The terms varus and valgus are both Latin, but confusingly, their Latin meanings conflict with their current usage. In current usage, as noted above, a varus deformity of the knee describes bowed legs, but in the original Latin, varus meant "knock-kneed." Similarly, while a valgus deformity of the knee would currently describe knocked knees, the original Latin meaning was "bow-legged" Application of these words in adjectival form to other portions of the body by the medical community has resulted in their definitions changing so that they now refer to the angle of the distal segment (i.e. valgus impaction in a Garden I femoral neck fracture). It is correct for a knock-kneed deformity to be called both a varus deformity at the hip (coxa vara) and a valgus deformity at the knee (genu valgum); although the common terminology is to simply refer to it as a valgus knee.When the terminology refers to a bone rather than a joint, the distal segment of the bone is being described. Thus, a varus deformity of the tibia (i.e. a mid-shaft tibial fracture with varus deformity) refers to the distal segment in a varus alignment compared to the proximal segment. Examples Hip: coxa vara — the angle between the head and the shaft of the femur is reduced, resulting in a limp. Knee: genu varum (from Latin genu = knee) — the tibia is turned inward in relation to the femur, resulting in a bowlegged deformity. Ankle: talipes varus (from Latin talus = ankle and pes = foot). A notable subtype is clubfoot or talipes equinovarus, which is where one or both feet are rotated inwards and downwards. Toe: hallux varus (Latin hallux = big toe) — inward deviation of the big toe away from the second toe. Elbows: cubitus varus (Latin cubitus = elbow) — turned inward elbows See also Valgus deformity References External links Canale & Beaty: Campbells Operative Orthopaedics, 11th ed. - 2007 - Mosby, An Imprint of Elsevier

Nervous

Nervous may refer to: nervousness Nervous system, a network of cells in an animals body that coordinates movement and the senses Nervous tissue, the cells of the nervous system that work in aggregate to transmit signals Music "Nervous" (Gene Summers song), 1958; covered by several performers "Nervous" (Gavin James song), 2016 "Nervous" (Shawn Mendes song), 2018 "Nervous", a song by K.Flay from Solutions, 2019 "Nervous", a song by L Devine, 2018 "Nervous", a song by Nick Jonas from Spaceman, 2021 Nervous Records, a UK record label Nervous Records (US), a US record label See also "Nervousness", a song by the Gigolo Aunts from Tales from the Vinegar Side Nervous Norvus (1912–1968), the performing name of Jimmy Drake Nervous shark, a species of requiem shark All pages with titles beginning with Nervous

Animal

Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in which their body consists of a hollow sphere of cells, the blastula, during embryonic development. Over 1.5 million living animal species have been described—of which around 1 million are insects—but it has been estimated there are over 7 million animal species in total. Animals range in length from 8.5 micrometres (0.00033 in) to 33.6 metres (110 ft). They have complex interactions with each other and their environments, forming intricate food webs. The scientific study of animals is known as zoology. Most living animal species are in Bilateria, a clade whose members have a bilaterally symmetric body plan. The Bilateria include the protostomes, containing animals such as nematodes, arthropods, flatworms, annelids and molluscs, and the deuterostomes, containing the echinoderms and the chordates, the latter including the vertebrates. Life forms interpreted as early animals were present in the Ediacaran biota of the late Precambrian. Many modern animal phyla became clearly established in the fossil record as marine species during the Cambrian explosion, which began around 539 million years ago. 6,331 groups of genes common to all living animals have been identified; these may have arisen from a single common ancestor that lived 650 million years ago. Historically, Aristotle divided animals into those with blood and those without. Carl Linnaeus created the first hierarchical biological classification for animals in 1758 with his Systema Naturae, which Jean-Baptiste Lamarck expanded into 14 phyla by 1809. In 1874, Ernst Haeckel divided the animal kingdom into the multicellular Metazoa (now synonymous for Animalia) and the Protozoa, single-celled organisms no longer considered animals. In modern times, the biological classification of animals relies on advanced techniques, such as molecular phylogenetics, which are effective at demonstrating the evolutionary relationships between taxa. Humans make use of many animal species, such as for food (including meat, milk, and eggs), for materials (such as leather and wool), as pets, and as working animals including for transport. Dogs have been used in hunting, as have birds of prey, while many terrestrial and aquatic animals were hunted for sports. Nonhuman animals have appeared in art from the earliest times and are featured in mythology and religion. Etymology The word "animal" comes from the Latin animalis, meaning having breath, having soul or living being. The biological definition includes all members of the kingdom Animalia. In colloquial usage, the term animal is often used to refer only to nonhuman animals. The term "metazoa" is from Ancient Greek μετα (meta, used to mean "later") and ζῷᾰ (zōia, plural of ζῷον zōion "animal"). Characteristics Animals have several characteristics that set them apart from other living things. Animals are eukaryotic and multicellular. Unlike plants and algae, which produce their own nutrients, animals are heterotrophic, feeding on organic material and digesting it internally. With very few exceptions, animals respire aerobically. All animals are motile (able to spontaneously move their bodies) during at least part of their life cycle, but some animals, such as sponges, corals, mussels, and barnacles, later become sessile. The blastula is a stage in embryonic development that is unique to animals, allowing cells to be differentiated into specialised tissues and organs. Structure All animals are composed of cells, surrounded by a characteristic extracellular matrix composed of collagen and elastic glycoproteins. During development, the animal extracellular matrix forms a relatively flexible framework upon which cells can move about and be reorganised, making the formation of complex structures possible. This may be calcified, forming structures such as shells, bones, and spicules. In contrast, the cells of other multicellular organisms (primarily algae, plants, and fungi) are held in place by cell walls, and so develop by progressive growth. Animal cells uniquely possess the cell junctions called tight junctions, gap junctions, and desmosomes.With few exceptions—in particular, the sponges and placozoans—animal bodies are differentiated into tissues. These include muscles, which enable locomotion, and nerve tissues, which transmit signals and coordinate the body. Typically, there is also an internal digestive chamber with either one opening (in Ctenophora, Cnidaria, and flatworms) or two openings (in most bilaterians). Reproduction and development Nearly all animals make use of some form of sexual reproduction. They produce haploid gametes by meiosis; the smaller, motile gametes are spermatozoa and the larger, non-motile gametes are ova. These fuse to form zygotes, which develop via mitosis into a hollow sphere, called a blastula. In sponges, blastula larvae swim to a new location, attach to the seabed, and develop into a new sponge. In most other groups, the blastula undergoes more complicated rearrangement. It first invaginates to form a gastrula with a digestive chamber and two separate germ layers, an external ectoderm and an internal endoderm. In most cases, a third germ layer, the mesoderm, also develops between them. These germ layers then differentiate to form tissues and organs.Repeated instances of mating with a close relative during sexual reproduction generally leads to inbreeding depression within a population due to the increased prevalence of harmful recessive traits. Animals have evolved numerous mechanisms for avoiding close inbreeding. Some animals are capable of asexual reproduction, which often results in a genetic clone of the parent. This may take place through fragmentation; budding, such as in Hydra and other cnidarians; or parthenogenesis, where fertile eggs are produced without mating, such as in aphids. Ecology Animals are categorised into ecological groups depending on how they obtain or consume organic material, including carnivores, herbivores, omnivores, detritivores, and parasites. Interactions between animals form complex food webs. In carnivorous or omnivorous species, predation is a consumer–resource interaction where a predator feeds on another organism (called its prey). Selective pressures imposed on one another lead to an evolutionary arms race between predator and prey, resulting in various anti-predator adaptations. Almost all multicellular predators are animals. Some consumers use multiple methods; for example, in parasitoid wasps, the larvae feed on the hosts living tissues, killing them in the process, but the adults primarily consume nectar from flowers. Other animals may have very specific feeding behaviours, such as hawksbill sea turtles primarily eating sponges. Most animals rely on the biomass and energy produced by plants through photosynthesis. Herbivores eat plant material directly, while carnivores, and other animals on higher trophic levels typically acquire it indirectly by eating other animals. Animals oxidize carbohydrates, lipids, proteins, and other biomolecules, which allows the animal to grow and to sustain biological processes such as locomotion. Animals living close to hydrothermal vents and cold seeps on the dark sea floor consume organic matter of archaea and bacteria produced in these locations through chemosynthesis (by oxidizing inorganic compounds, such as hydrogen sulfide).Animals originally evolved in the sea. Lineages of arthropods colonised land around the same time as land plants, probably between 510 and 471 million years ago during the Late Cambrian or Early Ordovician. Vertebrates such as the lobe-finned fish Tiktaalik started to move on to land in the late Devonian, about 375 million years ago. Animals occupy virtually all of earths habitats and microhabitats, including salt water, hydrothermal vents, fresh water, hot springs, swamps, forests, pastures, deserts, air, and the interiors of animals, plants, fungi and rocks. Animals are however not particularly heat tolerant; very few of them can survive at constant temperatures above 50 °C (122 °F). Only very few species of animals (mostly nematodes) inhabit the most extreme cold deserts of continental Antarctica. Diversity Size The blue whale (Balaenoptera musculus) is the largest animal that has ever lived, weighing up to 190 tonnes and measuring up to 33.6 metres (110 ft) long. The largest extant terrestrial animal is the African bush elephant (Loxodonta africana), weighing up to 12.25 tonnes and measuring up to 10.67 metres (35.0 ft) long. The largest terrestrial animals that ever lived were titanosaur sauropod dinosaurs such as Argentinosaurus, which may have weighed as much as 73 tonnes. Several animals are microscopic; some Myxozoa (obligate parasites within the Cnidaria) never grow larger than 20 µm, and one of the smallest species (Myxobolus shekel) is no more than 8.5 µm when fully grown. Numbers and habitats The following table lists estimated numbers of described extant species for all the animal groups, along with their principal habitats (terrestrial, fresh water, and marine), and free-living or parasitic ways of life. Species estimates shown here are based on numbers described scientifically; much larger estimates have been calculated based on various means of prediction, and these can vary wildly. For instance, around 25,000–27,000 species of nematodes have been described, while published estimates of the total number of nematode species include 10,000–20,000; 500,000; 10 million; and 100 million. Using patterns within the taxonomic hierarchy, the total number of animal species—including those not yet described—was calculated to be about 7.77 million in 2011. Evolutionary origin Animals are found as long ago as the Ediacaran biota, towards the end of the Precambrian, and possibly somewhat earlier. It had long been doubted whether these life-forms included animals, but the discovery of the animal lipid cholesterol in fossils of Dickinsonia establishes their nature. Animals are thought to have originated under low-oxygen conditions, suggesting that they were capable of living entirely by anaerobic respiration, but as they became specialized for aerobic metabolism they became fully dependent on oxygen in their environments.Many animal phyla first appear in the fossil record during the Cambrian explosion, starting about 539 million years ago, in beds such as the Burgess shale. Extant phyla in these rocks include molluscs, brachiopods, onychophorans, tardigrades, arthropods, echinoderms and hemichordates, along with numerous now-extinct forms such as the predatory Anomalocaris. The apparent suddenness of the event may however be an artefact of the fossil record, rather than showing that all these animals appeared simultaneously. That view is supported by the discovery of Auroralumina attenboroughii, the earliest known Ediacaran crown-group cnidarian (557–562 mya, some 20 million years before the Cambrian explosion) from Charnwood Forest, England. It is thought to be one of the earliest predators, catching small prey with its nematocysts as modern cnidarians do.Some palaeontologists have suggested that animals appeared much earlier than the Cambrian explosion, possibly as early as 1 billion years ago. Early fossils that might represent animals appear for example in the 665-million-year-old rocks of the Trezona Formation of South Australia. These fossils are interpreted as most probably being early sponges.Trace fossils such as tracks and burrows found in the Tonian period (from 1 gya) may indicate the presence of triploblastic worm-like animals, roughly as large (about 5 mm wide) and complex as earthworms. However, similar tracks are produced today by the giant single-celled protist Gromia sphaerica, so the Tonian trace fossils may not indicate early animal evolution. Around the same time, the layered mats of microorganisms called stromatolites decreased in diversity, perhaps due to grazing by newly evolved animals. Objects such as sediment-filled tubes that resemble trace fossils of the burrows of wormlike animals have been found in 1.2 gya rocks in North America, in 1.5 gya rocks in Australia and North America, and in 1.7 gya rocks in Australia. Their interpretation as having an animal origin is disputed, as they might be water-escape or other structures. Phylogeny Animals are monophyletic, meaning they are derived from a common ancestor. Animals are sister to the Choanoflagellata, with which they form the Choanozoa. The most basal animals, the Porifera, Ctenophora, Cnidaria, and Placozoa, have body plans that lack bilateral symmetry. Their relationships are still disputed; the sister group to all other animals could be the Porifera or the Ctenophora, both of which lack hox genes, important in body plan development.These genes are found in the Placozoa and the higher animals, the Bilateria. 6,331 groups of genes common to all living animals have been identified; these may have arisen from a single common ancestor that lived 650 million years ago in the Precambrian. 25 of these are novel core gene groups, found only in animals; of those, 8 are for essential components of the Wnt and TGF-beta signalling pathways which may have enabled animals to become multicellular by providing a pattern for the bodys system of axes (in three dimensions), and another 7 are for transcription factors including homeodomain proteins involved in the control of development.The phylogenetic tree indicates approximately how many millions of years ago (mya) the lineages split. Non-Bilateria Several animal phyla lack bilateral symmetry. Among these, the sponges (Porifera) probably diverged first, representing the oldest animal phylum. Sponges lack the complex organization found in most other animal phyla; their cells are differentiated, but in most cases not organised into distinct tissues. They typically feed by drawing in water through pores.The Ctenophora (comb jellies) and Cnidaria (which includes jellyfish, sea anemones, and corals) are radially symmetric and have digestive chambers with a single opening, which serves as both mouth and anus. They are sometimes placed together in the group Coelenterata because of common traits, not because of close relationships. Animals in both phyla have distinct tissues, but these are not organised into organs. They are diploblastic, having only two main germ layers, ectoderm and endoderm. The tiny placozoans are similar, but they do not have a permanent digestive chamber. Bilateria The remaining animals, the great majority—comprising some 29 phyla and over a million species—form a clade, the Bilateria, which have a bilaterally symmetric body plan. The Bilateria are triploblastic, with three well-developed germ layers, and their tissues form distinct organs. The digestive chamber has two openings, a mouth and an anus, and there is an internal body cavity, a coelom or pseudocoelom. These animals have a head end (anterior) and a tail end (posterior), a back (dorsal) surface and a belly (ventral) surface, and a left and a right side.Having a front end means that this part of the body encounters stimuli, such as food, favouring cephalisation, the development of a head with sense organs and a mouth. Many bilaterians have a combination of circular muscles that constrict the body, making it longer, and an opposing set of longitudinal muscles, that shorten the body; these enable soft-bodied animals with a hydrostatic skeleton to move by peristalsis. They also have a gut that extends through the basically cylindrical body from mouth to anus. Many bilaterian phyla have primary larvae which swim with cilia and have an apical organ containing sensory cells. However, over evolutionary time, descendant spaces have evolved which have lost one or more of each of these characteristics. For example, adult echinoderms are radially symmetric (unlike their larvae), while some parasitic worms have extremely simplified body structures.Genetic studies have considerably changed zoologists understanding of the relationships within the Bilateria. Most appear to belong to two major lineages, the protostomes and the deuterostomes. The basalmost bilaterians are the Xenacoelomorpha. Protostomes and deuterostomes Protostomes and deuterostomes differ in several ways. Early in development, deuterostome embryos undergo radial cleavage during cell division, while many protostomes (the Spiralia) undergo spiral cleavage. Animals from both groups possess a complete digestive tract, but in protostomes the first opening of the embryonic gut develops into the mouth, and the anus forms secondarily. In deuterostomes, the anus forms first while the mouth develops secondarily. Most protostomes have schizocoelous development, where cells simply fill in the interior of the gastrula to form the mesoderm. In deuterostomes, the mesoderm forms by enterocoelic pouching, through invagination of the endoderm.The main deuterostome phyla are the Echinodermata and the Chordata. Echinoderms are exclusively marine and include starfish, sea urchins, and sea cucumbers. The chordates are dominated by the vertebrates (animals with backbones), which consist of fishes, amphibians, reptiles, birds, and mammals. The deuterostomes also include the Hemichordata (acorn worms). Ecdysozoa The Ecdysozoa are protostomes, named after their shared trait of ecdysis, growth by moulting. They include the largest animal phylum, the Arthropoda, which contains insects, spiders, crabs, and their kin. All of these have a body divided into repeating segments, typically with paired appendages. Two smaller phyla, the Onychophora and Tardigrada, are close relatives of the arthropods and share these traits. The ecdysozoans also include the Nematoda or roundworms, perhaps the second largest animal phylum. Roundworms are typically microscopic, and occur in nearly every environment where there is water; some are important parasites. Smaller phyla related to them are the Nematomorpha or horsehair worms, and the Kinorhyncha, Priapulida, and Loricifera. These groups have a reduced coelom, called a pseudocoelom. Spiralia The Spiralia are a large group of protostomes that develop by spiral cleavage in the early embryo. The Spiralias phylogeny has been disputed, but it contains a large clade, the superphylum Lophotrochozoa, and smaller groups of phyla such as the Rouphozoa which includes the gastrotrichs and the flatworms. All of these are grouped as the Platytrochozoa, which has a sister group, the Gnathifera, which includes the rotifers.The Lophotrochozoa includes the molluscs, annelids, brachiopods, nemerteans, bryozoa and entoprocts. The molluscs, the second-largest animal phylum by number of described species, includes snails, clams, and squids, while the annelids are the segmented worms, such as earthworms, lugworms, and leeches. These two groups have long been considered close relatives because they share trochophore larvae. History of classification In the classical era, Aristotle divided animals, based on his own observations, into those with blood (roughly, the vertebrates) and those without. The animals were then arranged on a scale from man (with blood, 2 legs, rational soul) down through the live-bearing tetrapods (with blood, 4 legs, sensitive soul) and other groups such as crustaceans (no blood, many legs, sensitive soul) down to spontaneously generating creatures like sponges (no blood, no legs, vegetable soul). Aristotle was uncertain whether sponges were animals, which in his system ought to have sensation, appetite, and locomotion, or plants, which did not: he knew that sponges could sense touch, and would contract if about to be pulled off their rocks, but that they were rooted like plants and never moved about.In 1758, Carl Linnaeus created the first hierarchical classification in his Systema Naturae. In his original scheme, the animals were one of three kingdoms, divided into the classes of Vermes, Insecta, Pisces, Amphibia, Aves, and Mammalia. Since then the last four have all been subsumed into a single phylum, the Chordata, while his Insecta (which included the crustaceans and arachnids) and Vermes have been renamed or broken up. The process was begun in 1793 by Jean-Baptiste de Lamarck, who called the Vermes une espèce de chaos (a chaotic mess) and split the group into three new phyla: worms, echinoderms, and polyps (which contained corals and jellyfish). By 1809, in his Philosophie Zoologique, Lamarck had created 9 phyla apart from vertebrates (where he still had 4 phyla: mammals, birds, reptiles, and fish) and molluscs, namely cirripedes, annelids, crustaceans, arachnids, insects, worms, radiates, polyps, and infusorians.In his 1817 Le Règne Animal, Georges Cuvier used comparative anatomy to group the animals into four embranchements ("branches" with different body plans, roughly corresponding to phyla), namely vertebrates, molluscs, articulated animals (arthropods and annelids), and zoophytes (radiata) (echinoderms, cnidaria and other forms). This division into four was followed by the embryologist Karl Ernst von Baer in 1828, the zoologist Louis Agassiz in 1857, and the comparative anatomist Richard Owen in 1860.In 1874, Ernst Haeckel divided the animal kingdom into two subkingdoms: Metazoa (multicellular animals, with five phyla: coelenterates, echinoderms, articulates, molluscs, and vertebrates) and Protozoa (single-celled animals), including a sixth animal phylum, sponges. The protozoa were later moved to the former kingdom Protista, leaving only the Metazoa as a synonym of Animalia. In human culture Practical uses The human population exploits a large number of other animal species for food, both of domesticated livestock species in animal husbandry and, mainly at sea, by hunting wild species. Marine fish of many species are caught commercially for food. A smaller number of species are farmed commercially. Humans and their livestock make up more than 90% of the biomass of all terrestrial vertebrates, and almost as much as all insects combined.Invertebrates including cephalopods, crustaceans, and bivalve or gastropod molluscs are hunted or farmed for food. Chickens, cattle, sheep, pigs, and other animals are raised as livestock for meat across the world. Animal fibres such as wool are used to make textiles, while animal sinews have been used as lashings and bindings, and leather is widely used to make shoes and other items. Animals have been hunted and farmed for their fur to make items such as coats and hats. Dyestuffs including carmine (cochineal), shellac, and kermes have been made from the bodies of insects. Working animals including cattle and horses have been used for work and transport from the first days of agriculture.Animals such as the fruit fly Drosophila melanogaster serve a major role in science as experimental models. Animals have been used to create vaccines since their discovery in the 18th century. Some medicines such as the cancer drug Yondelis are based on toxins or other molecules of animal origin. People have used hunting dogs to help chase down and retrieve animals, and birds of prey to catch birds and mammals, while tethered cormorants have been used to catch fish. Poison dart frogs have been used to poison the tips of blowpipe darts. A wide variety of animals are kept as pets, from invertebrates such as tarantulas and octopuses, insects including praying mantises, reptiles such as snakes and chameleons, and birds including canaries, parakeets, and parrots all finding a place. However, the most kept pet species are mammals, namely dogs, cats, and rabbits. There is a tension between the role of animals as companions to humans, and their existence as individuals with rights of their own. A wide variety of terrestrial and aquatic animals are hunted for sport. Symbolic uses Animals have been the subjects of art from the earliest times, both historical, as in Ancient Egypt, and prehistoric, as in the cave paintings at Lascaux. Major animal paintings include Albrecht Dürers 1515 The Rhinoceros, and George Stubbss c. 1762 horse portrait Whistlejacket. Insects, birds and mammals play roles in literature and film, such as in giant bug movies.Animals including insects and mammals feature in mythology and religion. In both Japan and Europe, a butterfly was seen as the personification of a persons soul, while the scarab beetle was sacred in ancient Egypt. Among the mammals, cattle, deer, horses, lions, bats, bears, and wolves are the subjects of myths and worship. The signs of the Western and Chinese zodiacs are based on animals. See also Animal attacks Animal coloration Ethology Fauna List of animal names Lists of organisms by population Notes References External links Tree of Life Project Archived 12 June 2011 at the Wayback Machine Animal Diversity Web – University of Michigans database of animals ARKive – multimedia database of endangered/protected species

Diphyllobothriasis

Diphyllobothriasis is the infection caused by tapeworms of the genus Diphyllobothrium (commonly D. latum and D. nihonkaiense). Diphyllobothriasis mostly occurs in regions where raw fish is regularly consumed; those who consume raw fish are at risk of infection. The infection is often asymptomatic and usually presents only with mild symptoms, which may include gastrointestinal complaints, weight loss, and fatigue. Rarely, vitamin B12 deficiency (possibly leading to anaemia) and gastrointestinal obstructions may occur. Infection may be long-lasting in absence of treatment. Diphyllobothriasis is generally diagnosed by looking for eggs or tapeworm segments in passed stool. Treatment with antiparasitic medications is straightforward, effective, and safe. Signs and symptoms Most infections (~80%) are asymptomatic. Infections may be long-lasting, persisting for many years or decades (up to 25 years) if untreated. Symptoms (when present) are generally mild. Manifestations may include abdominal pain and discomfort, diarrhea, vomiting, constipation, weight loss, and fatigue. Additional symptoms have been reported/described, including dyspepsia, abdominal distension (commonly as presenting complaint), headache, myalgia, and dizziness. Complications While the infection is generally mild, complications may occur. Complications are predicated on parasite burden, and are generally related to vitamin B12 deficiency and related health conditions. Vitamin B12 deficiency and anaemia Vitamin B12 deficiency with subsequent megaloblastic anaemia (which is indistinguishable from pernicious anaemia) may occur in some instances of the disease. Anaemia may in turn result in subacute combined degeneration of the spinal cord and cognitive decline.D. latum competes with the host for vitamin B12 absorption, absorbing some 80% of dietary intake and causing deficiency and megaloblastic anaemia in some 40% of cases. Vitamin B12 uptake is enabled by the position of the parasite which usually lodges in the jejunum. Vitamin B12 deficiency is - according to research - conversely seldom seen in D. pacificum infection. Gastrointestinal obstructions Rarely, massive infections may result in intestinal obstruction. Migration of proglottids can cause cholecystitis or cholangitis. Cause Diphyllobothriasis is caused by infection by several species of the Diphyllobothrium genus. Transmission Humans are one of the definitive hosts of Diphyllobothrium tapeworms, along with other carnivores; fish-eating mammals (including canids, felids, and bears), marine mammals (dolphins, porpoises, and whales), and (a few) birds (e.g. gulls) may also serve as definitive hosts.Definitive hosts release eggs in faeces; the eggs then mature in ~18–20 days if under favourable conditions. Crustaceans serve as the first intermediate hosts, and Diphyllobothrium larvae develop. The larvae are released when crustaceans are consumed by predators, which serve as second intermediate hosts (these are mostly small fish). Larvae move into deeper tissues in the second intermediate host. Second intermediate hosts do not serve as an important source of infection of humans as these are not regularly consumed raw. Consumption of infected second intermediate hosts by larger predatory fish, which serve as paratenic hosts; the parasites thereupon migrate into the musculature awaiting consumption by definitive hosts in which adult tapeworms will then finally develop in the small intestine to release up to a million immature eggs per day per parasite. Hosts begin to release eggs 5–6 weeks after infection. Pathophysiology Tapeworms develop in the small intestine. Adults attach to the intestinal mucosa. Adult tapeworms may grow to over 10m in length and may constitute of over 3,000 proglottids which contain sets of male and female reproductive organs, allowing for high fecundity. Eggs appear in the faeces 5–6 weeks after infection.D. latum tapeworms are the longest and typically reach a length of 4-15m, but may grow up to 25m in length within the human intestine. Growth rate may exceed 22 cm/day. D. latum tapeworms feature an anterior end (scolex) equipped with attachment grooves on the dorsal and ventral surfaces. Host-parasite interactions Diphyllobothriasis is postulated to cause changes in neuromodulator concentrations in host tissue and serum. D. latum infection has been shown to cause local changes in the host, leading to altered GI function (including motility) via neuroendocrine modulation.Diphyllobothriasis causes mast cell and eosinophil degranulation, leading to pro-inflammatory cytokine release. Diagnosis Infection may be suspected based upon a patients occupation, hobbies, eating habits, and travel history. During diagnostic procedures, standard safety precautions apply. Eggs are not directly infectious to humans (in contrast to some other tapeworm species). Microscopy Diagnosis is usually made by identifying proglottid segments, or characteristic eggs in the faeces. Eggs are usually numerous and can be demonstrated without concentration techniques. Morphologic comparison with other intestinal parasites may be employed as a further diagnostic approach.These simple diagnostic techniques are able to identify the nature of the infection to the genus level, which is usually sufficient in a clinical setting. Though it is difficult to identify the eggs or proglottids to the species level, the distinction is of little clinical importance because - like most adult tapeworms in the intestine - all members of the genus respond to the same treatments. Treatment may distort morphological features of expelled pathogen tissues and complicate subsequent morphological diagnosis attempts. Genetic identification When the exact species need be determined (e.g. in epidemiological studies), restriction fragment length polymorphisms can be effectively used. PCR can be performed on samples of purified eggs, or on native fecal samples following sonication of the eggs to release their contents. Molecular identification is currently generally only used in research. Radiography A potential diagnostic tool and treatment is the contrast medium gastrografin which, when introduced into the duodenum, allows both visualization of the parasite, and has also been shown to cause detachment and passing of the whole parasite. Prevention Ingestion of raw freshwater fish should be avoided. Adequate cooking or freezing of freshwater fish will destroy the encysted fish tapeworm larvae. Fish that is thoroughly cooked, brined, or frozen at -10 °C for 24–48 hours can also be consumed without risk of D. latum infection. Public health information campaigns may be employed to educate the public about the risks of consuming improperly prepared fish. Because human feces are an important mechanism for spreading eggs, proper disposal of sewage can reduce fish (and therefore human) infections. Prevention of water contamination may be achieved both by raising public awareness of the dangers of defecating in recreational bodies of water and by implementation of basic sanitation measures and screening and successful treatment of people infected with the parasite. Treatment Upon diagnosis, treatment is simple and effective.Praziquantel The standard treatment for diphyllobothriasis (as well as many other tapeworm infections) is a single dose of praziquantel, 5–10 mg/kg orally once for both adults and children. Praziquantel is not FDA-approved for this indication. Praziquantel has few side effects, many of which are similar to the symptoms of diphyllobothriasis.Niclosamide An alternative treatment is niclosamide, 2 g orally once for adults or 50 mg/kg (max 2 g) for children. Niclosamide is not available for human or even animal use in the United States. Side effects of niclosamide are very rare due to the fact that the medication is not absorbed in the gastrointestinal tract.Other Reportedly, albendazole can also be effective. Gastrografin may be potentially used both as a diagnostic and therapeutic; when introduced into the duodenum it allows for the visualization of the parasite, and has also been shown to cause detachment and passing of the whole worm. During the 1940s, the preferred treatment was 6 to 8 grams of oleoresin of aspidium, which was introduced into the duodenum via a Rehfuss tube. Epidemiology People at high risk for infection have traditionally been those who regularly consume raw fish. While people of any gender or age may fall sick, the majority of identified cases occurred in middle-aged men. Geographical distribution Diphyllobothriasis occurs in areas where lakes and rivers coexist with human consumption of raw or undercooked freshwater fish. Such areas are found in Europe, newly independent states of the former Soviet Union, North America, Asia, Uganda, Peru (because of ceviche), and Chile. Many regional cuisines include raw or undercooked food, including sushi and sashimi in Japanese cuisine, carpaccio di persico in Italian, tartare maison in French-speaking populations, ceviche in Latin American cuisine and marinated herring in Scandinavia. With emigration and globalization, the practice of eating raw fish in these and other dishes has brought diphyllobothriasis to new parts of the world and created new endemic foci of disease.Infections in Europe and North America were traditionally associated with Jewish women due to the practice of tasting bits of uncooked fish during preparation of the gefilte fish dish, and also occurred in Scandinavian women for the same reason. Diphyllobothriasis was thus also referred to as the "Jewish housewifes disease" or the "Scandinavian housewifes disease". Japan Diphyllobothriasis nihonkaiense was once endemic to coastal provinces of central and northern Japan, where salmon fisheries thrived. In recent decades, regions with endemic diphyllobothriasis nihonkaiense have disappeared from Japan, though cases continue to be reported among urbanites who consume sushi or sashimi. In Kyoto, it is estimated that the average annual incidence in the past 20 years was 0.32/100,000, and that in 2008 was 1.0 case per 100,000 population, suggesting that D. nihonkaiense infection is equally as prevalent in Japan as D. latum is in some European countries. United States The disease is rare in the United States. History The fish tapeworm has a long documented history of infecting people who regularly consume fish and especially those whose customs include the consumption of raw or undercooked fish. In the 1970s, most of the known cases of diphyllobothriasis came from Europe (5 million cases), and Asia (4 million cases) with fewer cases coming from North America and South America, and no reliable data on cases from Africa or Australia. Despite the relatively small number of cases seen today in South America, some of the earliest archeological evidence of diphyllobothriasis comes from sites in South America. Evidence of Diphyllobothrium spp. has been found in 4,000- to 10,000-year-old human remains on the western coast of South America. There is no clear point in time when Diphyllobothrium latum and related species were “discovered” in humans, but it is clear that diphyllobothriasis has been endemic in human populations for a very long time. Due to the changing dietary habits in many parts of the world, autochthonous, or locally acquired, cases of diphyllobothriasis have recently been documented in previously non-endemic areas, such as Brazil. In this way, diphyllobothriasis represents an emerging infectious disease in certain parts of the world where cultural practices involving eating raw or undercooked fish are being introduced. References External links "Diphyllobothriasis". CDC – DPDx – Laboratory Identification of Parasitic Diseases of Public Health Concern. 2013-11-29. Retrieved 2015-09-05.

Sequela

A sequela (UK: , US: ; usually used in the plural, sequelae ) is a pathological condition resulting from a disease, injury, therapy, or other trauma. Derived from the Latin word, meaning “sequel”, it is used in the medical field to mean a complication or condition following a prior illness or disease.A typical sequela is a chronic complication of an acute condition—in other words, a long-term effect of a temporary disease or injury—which follows immediately from the condition. Sequelae differ from late effects, which can appear long after—even several decades after—the original condition has resolved. In general, non-medical usage, the terms sequela and sequelae mean consequence and consequences. Examples and uses Chronic kidney disease, for example, is sometimes a sequela of diabetes; "chronic constipation" or more accurately "obstipation" (that is, inability to pass stool or gas) is a sequela to an intestinal obstruction; and neck pain is a common sequela of whiplash or other trauma to the cervical vertebrae. Post-traumatic stress disorder may be a psychological sequela of rape. Sequelae of traumatic brain injury include headache, dizziness, anxiety, apathy, depression, aggression, cognitive impairments, personality changes, mania, and psychosis. COVID-19 is also known to cause post-acute sequelae, known as long COVID, post-COVID syndrome, or post-acute sequelae of COVID-19 (PASC). This refers to the continuation of COVID-19 symptoms or the development of new ones, four or more weeks after the initial infection; these symptoms may persist for weeks and months. Post-COVID syndrome can occur in individuals who were asymptomatic for COVID, as well as those ranging from mild illness to severe hospitalization. These most commonly reported sequelae include fatigue, shortness of breath, chest pain, loss of smell, and brain fog; symptoms drastically range, from mild illness to severe impairment.Some conditions may be diagnosed retrospectively from their sequelae. An example is pleurisy. Other examples of sequelae include those following neurological injury; including aphasia, ataxia, hemi- and quadriplegia, and any number of other changes that may be caused by neurological trauma. Note that these pathologies can be related to both physical and chemical traumas, as both can cause lingering neuronal damage. The phrase status post, abbreviated in writing as s/p, is used to discuss sequelae with reference to their cause. Clinicians typically use the phrase to refer to acute traumatic conditions. For example: "the patient had neck pain status post a motor vehicle accident". Rheumatic fever is a non-suppurative sequela of a primary infection of group A Streptococcus bacteria. Glomerulonephritis can also be a non-suppurative sequela of Streptococcus pyogenes. References Further reading Lindsay, James (1997). "Chronic Sequelae of Foodborne Disease". Emerging Infectious Diseases. 3 (4): 443–452. doi:10.3201/eid0304.970405. PMC 2640087. PMID 9366595. External links Traumatic causes of Tempormandibular Joints Disorder (dysfunction)

Buried penis

Buried penis (also known as hidden penis or retractile penis) is a congenital or acquired condition in which the penis is partially or completely hidden below the surface of the skin. A buried penis can lead to urinary difficulties, poor hygiene, infection, and inhibition of normal sexual function.Buried penis is different than micropenis, which is an abnormally small, normally structured penis with a stretched penile length of less than 2.5 standard deviations below the mean for age or stage of sexual development of the patient. History Buried penis was first described by Edward Lawrence Keyes in 1919 as the apparent absence of the penis due to the penis being buried beneath the skin of the abdomen, thigh, or scrotum. Further research was done by Maurice Campbell in 1951, when he reported on the penis being buried beneath subcutaneous fat of the scrotum, perineum, hypogastrium, and thigh. Causes Congenital Congenital causes can include the maldevelopment of the penile shaft with a lack of attachments of the shaft skin to the penile shaft. While rare, it can include an abnormally large pubic fat pad and firm tissue that pulls the penis inward. Acquired Obesity While not every obese male has the buried penis condition, 87% of men that received surgical treatment for buried penis were reported to be obese. Significant overlying abdominal fat can also create an environment that encourages bacterial and fungal growth. Obesity can also increase the likelihood of the development of type II diabetes mellitus, which is characterized by increase susceptibility to infections, making it difficult to successfully and promptly manage the buried penis condition. Such recurring infections can also lead to scar contracture, which can cause the prepubic skin to shift over the shaft and glans, thus invaginating the shafts skin and leading to a buried penis. </ref> Penoscrotal lymphodema While an uncommon cause, penoscrotal lymphodema causes a deformity of the shaft and scrotum, resulting in a buried penis. Overly aggressive circumcision In some cases of circumcision, too much foreskin is removed or the suture line constricts, causing cicatricial scarring, which can trap the penis in the remaining foreskin or push the penis into the suprapubic area and lead to a buried penis. Balanitis xerotica obliterans (BXO) BXO is a chronic inflammatory dermatological process that causes sclerosis of the glans, shaft, prepuce, or urethra. This can result in a cicatrix of the distal penis and its entrapment. Dysgenic dartos Dysgenic dartos is a condition characterized by a lack of dorsal support together with the hypermobility of the ventral skin and the lack of proper attachment between the dartos and the penis. This can enable the penis to "telescope" into the scrotum, thus creating a buried penis. Treatment The condition may resolve itself without any intervention in very young children; however, patients may eventually need definitive reconstructive surgery. Urgent surgery may be necessary if infection is present. Congenitial buried penis can be corrected surgically in childhood by anchoring the corpora cavernosa to dartos bundles at the penile base. While weight loss may be of help to morbidly obese children and adults, it usually does not resolve the problem completely.Surgical options could include the detachment of the ligaments connecting the base of the penis to the pubic bone; the performance of skin grafts to cover areas of the penis requiring additional skin; liposuction using catheters to suck out fat cells under the skin from the area around the penis; an abdominoplasty in which excess fat and skin from the region are removed; an escutheonectomy in which the pad of fat just above the pubic area is removed; or a panniculectomy in which the panniculus, excess tissue, and skin that hangs over the genitals and thighs are removed. In a video demonstrating the use of a panniculectomy in the repair of adult buried penis, Dr. Bryan Voelzke and his colleagues emphasized the need to tack the suprapubic fat pad to the periosteum of the symphysis pubis as well as the importance of not pulling down the peno-scrotal junction and peno-abdominal junction just in order to further expose the penis.King IC, Tahir A, Ramanathan C, and Siddiqui H developed a modified treatment algorithm employing a single surgical technique consisting primarily of scar release and the mobilization of the skin of the penis.An article published in August 2019 by Dr. James J. Elist reported that a procedure involving the insertion of a subcutaneous soft silicone penile implant was successful in reversing the condition of adult acquired buried penis. See also Micropenis Phalloplasty Webbed penis References External links Examples

Circumvallate placenta

Circumvallate placenta is a rare condition affecting about 1-2% of pregnancies, in which the amnion and chorion fetal membranes essentially "double back" on the fetal side around the edges of the placenta. After delivery, a circumvallate placenta has a thick ring of membranes on its fetal surface. Circumvallate placenta is a placental morphological abnormality associated with increased fetal morbidity and mortality due to the restricted availability of nutrients and oxygen to the developing fetus. Physicians may be able to detect a circumvallate placenta during pregnancy by using an ultrasound. However, in other cases, a circumvallate placenta is not identified until delivery of the baby. Circumvallate placenta can increase the risk of associated complications such as preterm delivery and placental abruption. Occasionally, a circumvallate placenta can also increase the risk of neonatal death and emergency caesarean section. Although there is no existing treatment for circumvallate placenta, physicians can attempt to minimize the effects of complications, if they occur, through frequent fetal monitoring and, if necessary, emergency cesarean section.In a circumvallate placenta, the chorionic plate, which forms the fetal surface of the placenta, tends to be smaller than the basal plate, which forms the maternal surface of the placenta. This results in the elevation of the placental margin and the appearance of an annular shape. The fetal surface is divided into a central depressed zone surrounded by a thickened white ring which is incomplete. The ring is situated at varying distances from the margin, or edges, of the placenta. This thick ring of membranes is composed of a double fold of amnion and chorion with degenerated decidua vera and fibrin in between. Blood vessels, supplying nutrients and carrying waste products to and from the developing fetus, radiate from the umbilical cord insertion to as far as the ring of membranes, and then disappears from view. Signs & Symptoms A circumvallate placenta does not always induce associated symptoms during pregnancy, making it extremely difficult to diagnose a circumvallate placenta in asymptomatic mothers. In symptomatic mothers, physicians may be able to detect a circumvallate placenta based on the presentation of the following signs. Vaginal bleeding: A circumvallate placenta can increase the risk of frequent vaginal bleeding during the first trimester of pregnancy. In a study conducted with 92 women with a circumvallate placenta, it was concluded that incidences of vaginal bleeding were significantly higher in women with a circumvallate placenta during all three trimesters when compared to the control group. However, a noted limitation of the study considered by the researchers was that because the study included such a small number of women, the obtained results may not be fully representative of the general population. Because the chorionic plate is much smaller than the basal plate in a circumvallate placenta, vaginal bleeding tends to occur at this site where the placenta is exposed and uncovered. In mothers presenting with vaginal bleeding, circumvallate placenta should be suspected as a possible cause of the vaginal bleeding. Inhibited fetal growth: Fetuses tend to develop more slowly when associated with a circumvallate placenta, largely due to the reduced supply of blood and nutrients from mother to fetus. Physicians will order tests to determine the cause of inhibited fetal growth when a developing fetus does not meet growth expectations during the course of the pregnancy. Premature rupture of membranes (PROM): PROM happens when the protective covering of the amniotic sac ruptures before the onset of labor and delivery. If PROM occurs within the first 37 weeks of pregnancy, it is termed preterm premature rupture of membranes (PPROM). PROM itself has many causes and risk factors. When PROM occurs along with vaginal bleeding in the second trimester of pregnancy, it is suspected that a mother likely has a circumvallate placenta. Complications Circumvallate placenta has also been associated with a higher incidence of complications including placental abruption, low birth weight, premature delivery, perinatal death, and fetal abnormalities. Low birth weight: Lack of proper nutrition and blood flow to the fetus during pregnancy often results in decreased weight of the baby at birth. Placenta abruption: Placenta abruption, in which the placenta divides from the wall of the uterus prior to birth, can have severe outcomes for a mother and her baby. Such consequences include vaginal bleeding, decreased birth weight, preterm delivery, and stillbirth. Significant vaginal bleeding can induce maternal anemia and dangerously low blood pressure. Oligohydramnios: Insufficiency of proper volumes of amniotic fluid, a condition called oligohydramnios, can also occur as a result of a circumvallate placenta. Amniotic fluid is essential to normal fetal movement, fetal organ development, and cushioning of the fetus within the mothers uterus. It is also imperative in preventing umbilical cord compression so that the fetus is able to obtain nourishment and oxygenation from its mother. Premature delivery: Premature birth of the fetus occurs at less than 37 weeks of gestation, compared to full-term delivery at about 40 weeks. Miscarriage: Loss of a fetus prior to birth via miscarriage can transpire if any of the above complications occur without prompt intervention and treatment. Cause Unfortunately, there is no known cause of circumvallate placenta and no major preventative measures that can be taken to minimize the risk of developing a circumvallate placenta. Circumvallate placenta is not a genetic disorder. Some potential causes of circumvallate placenta include reduced amniotic fluid pressure, circumferential hemorrhage, and superficial or deep implantation of the embryo within the uterine wall, although these potential causes are still not well-understood in terms of their relation to circumvallate placenta.High-risk pregnancies are described as pregnancies in which a mother, the fetus, or both are put at a higher risk for developing pregnancy complications before, during, or after birth. Risk factors such as hypertensive medical conditions, maternal age, and substance use are just some of the things that can put a woman at an increased risk for developing circumvallate placenta and/or any other complications. Risk factors Hypertensive disorders Women entering a pregnancy with hypertension are considered to be put at a higher risk for preeclampsia or eclampsia during the course of their pregnancy. Hypertensive disorders, like hypertension, have been found to affect about 10% of pregnancies in the United States and have resulted in about 6.8% of maternal deaths from 2011 to 2015. High blood pressure during pregnancy can potentially damage maternal organ systems such as the liver or the kidneys, which can be life-threatening. To prevent preeclampsia or eclampsia from developing in pregnancy, women with hypertension can be prescribed anti-hypertensive medications during pregnancy and are advised to monitor their blood pressure throughout the course of pregnancy. Maternal age Another risk factor for developing any pregnancy complications is maternal age. Advanced maternal age, considered to be when a woman enters pregnancy at age 35 or above, has also been linked to increased risk of maternal mortality, preeclampsia, restricted fetal growth, fetal distress, and a variety of other pregnancy complications. Conversely, teenage pregnancy is also associated with increased risk of endometriosis, postpartum hemorrhage, and mild preeclampsia, when compared with pregnant mothers in their 20s. Genetically, the long period of time between meiotic arrest of the egg gamete as a fetus and each ovulation cycle occurring after the onset of female puberty in teenage years can potentially contribute to the increased risk for pregnancy complications in mothers who are age 35 or older at time of pregnancy. Substance use Further, yet another factor inducing adverse complications in pregnancy is substance use status. Nicotine, alcohol, and marijuana are the most common substances used during pregnancies. Substance use in pregnancy is concerning because of its alarming association with other risk factors, such as mental illness. Depression alone has been associated within increased risk for preeclampsia, gestational diabetes, hypertension, premature birth, and low birth weight. Women with substance use disorders tend to live in areas that are unable to provide quality prenatal care or proper management of their psychiatric conditions. As a result of improper management of psychiatric illnesses, substances are abused during pregnancy, potentially causing harm to both the mother and the fetus. Some pregnancy complications that can occur as a result of substance use in pregnancy are fetal alcohol syndrome and neonatal abstinence disorder.Women with these risk factors are recommended additional surveillance during pregnancy to monitor fetal development and to be able to detect fetal, placental, or umbilical cord abnormalities as early as possible. Pathophysiology/Mechanism The placenta is a transient organ developed during pregnancy that facilitates nutrient, gas, and waste exchange between a mother and a developing fetus. Placental abnormalities, such as circumvallate placenta, can harm a developing fetus, as normal exchange of materials between a mother and a developing fetus is impaired. With placental abnormalities, a developing fetus is unable to receive the vital materials that it needs for proper development, resulting in the possibility of pregnancy complications, birth defects, and/or death of the fetus. In a normal placenta, there is a smooth transition from the parenchymal villous chorion to the membranous chorion at the border of the placental plate. Fetal blood vessels subdivide from the umbilical cord and spread diagonally throughout the parenchyma towards the edge of the placental plate.In a circumvallate placenta, the membranes often become restrained due to marginal infarct, hemorrhage, or fibrin depositing. This results in the reduction in size of the chorionic plate of the placenta, further causing the membranes on the fetal side to fold backward on themselves. The parenchymal villous chorion continues to proliferate beyond the tethered membranes and appears to protrude outward. The fetal blood vessels are directed downward and then horizontally in order to provide blood flow to the most peripheral parts of the placental plate extending beyond the tethered membranes.Since a portion of the placenta tends to become exposed in a circumvallate placenta, due to the reduced size of the chorionic plate, vaginal bleeding is more likely to occur at this site of exposure. Likewise, inhibited fetal growth can also ensue due to the decreased exchange of nutrients and waste between mother and fetus, since the fetus is unable to sustain necessary nutritional demands for proper fetal development. Premature rupture of membranes often occurs as a result of infection in the uterus, which can be caused by the occurrence vaginal bleeding. Therefore, placental abnormalities such as circumvallate placenta can be extremely detrimental in causing the onset of associated conditions. Diagnosis In some cases, a physician may be able to diagnose a circumvallate placenta via ultrasound during one of many routine ultrasound screenings. In most cases, a circumvallate placenta is not discovered until physical examination of the placenta after delivery of the fetus. For this reason, circumvallate placenta is very difficult to diagnose during pregnancy. On ultrasound, a normal placenta should appear complete and uniform, with the fetal surface of the placenta appearing slightly shiny and translucent. The appearance of a circumvallate placenta on ultrasound may present with irregular edges, uplifted margins, or placental sheets. In a study conducted in 1994, 62 healthy pregnant women were examined with placental sonography for detection of circumvallate placenta. Of the five experienced sonologists who interpreted the placental ultrasounds, all were unable to properly detect and diagnose circumvallate placenta, revealing the difficult nature of circumvallate placenta recognition. Further, these findings indicate that prenatal sonographic criteria used for detection of circumvallate placenta are not reliable enough for screening purposes. Complete circumvallate placenta involves morphological abnormality of the entire dimension of the placenta, while partial circumvallate placenta does not involve the entire placenta but rather a portion of the placenta. Complete circumvallate placenta is very rare, occurring within about 1% of pregnancies, and has been noted to increase the risks of associated complications such as placental abruption, premature childbirth, premature rupture of membranes, perinatal death, and congenital abnormalities. Partial circumvallate placenta is more common but is not found to be as clinically significant as complete circumvallate placenta.The accurate diagnosis of circumvallate placenta during pregnancy can have significant implications in the recognition of patients who are at risk of complications. Although the ability of sonography to accurately diagnosis circumvallate placenta during pregnancy is quite limited, research studies continue to emerge at the possibility of doing so. Treatment/Management Although there is no cure or specific treatment for restoration of the circumvallate placenta, there are ways to decrease the risks of possible complications prior to birth or attempt to manage complications if they develop. If circumvallate placenta is diagnosed during pregnancy, physicians may offer recommendations to reduce the risks of associated complications such as lower birth weight and placental abruption.Decreased birth weight is a major concern associated with circumvallate placenta. Infants born with birth weights that are lower than expected per their gestational age oftentimes end up requiring extra support in the neonatal intensive care unit (NICU). To assist in the monitoring of appropriate fetal growth, a physician may recommend more frequent growth checks during pregnancy if circumvallate placenta is suspected. If a fetus is not growing satisfactorily, premature delivery, via vaginal delivery or caesarean section, may be recommended, with C-section being more favorable compared to vaginal delivery.In women experiencing a placental abruption associated with circumvallate placenta, physicians will normally advocate for frequent growth checks, hospital bed rest, early delivery, and, if necessary, emergency C-section. Likewise, IV fluids and blood transfusions can also be given to patients with a placental abruption in attempts to increase blood pressure and minimize the effects of severe blood loss.If oligohydramnios occurs as a result of a circumvallate placenta, a treatment called amnioinfusion may be considered to replenish the amount of lost amniotic fluid within the amniotic sac. Amnioinfusion may help in preventing underdevelopment of the lungs.If diagnosed with a circumvallate placenta, consistent fetal monitoring by a licensed physician can help to prevent and/or reduce the effects of associated complications that may occur. Additionally, healthy lifestyle choices, a well-balanced and nutritious diet, adequate rest, and cessation of alcohol and tobacco products can also help to prevent the incidence of a circumvallate placenta and its associated complications. If diagnosed with a circumvallate placenta, in association with other threatening pregnancies complications, emergency cesarean section will most likely be suggested by a physician. Prognosis Unfortunately, there is currently not a cure available for circumvallate placenta. While some evidence suggests that a circumvallate placenta can increase the risk of complication during pregnancy, other research suggests this increased risk is marginal. Sadly, circumvallate placenta can occasionally result in infant death depending on the severity of the complications encountered. In other cases, circumvallate placenta can result in premature birth of infants who are otherwise healthy after being monitored in the neonatal intensive care unit for a period of time after birth. Therefore, proper medical care and monitoring are crucial in attempting to minimize the likelihood of complications. In other cases, patients diagnosed with circumvallate placenta are able to carry their babies until term or near-term. Epidemiology Circumvallate placenta is a very rare condition affecting pregnant women. This condition is a placental morphological abnormality, with the placenta being formed during the early periods of pregnancy. Women are able to become pregnant with the onset of ovulation and menstruation in early adolescence, with most women becoming pregnant during adulthood. Circumvallate placenta is currently known to affect about 1-2% of pregnancies. It is not virally transmissible to other individuals, nor can it be transferred through contact or respiration.There are no specific racial or ethnic groups that are more predisposed to acquiring a circumvallate placenta during pregnancy, however, as with all pregnancies, there are general risks factors that can put a pregnant woman at risk for complications, including circumvallate placenta. Notably, certain pregnancy complications, such as preeclampsia, tend to be almost three times as fatal in African American women compared to non-Hispanic white women, even though both groups tend to experience preeclampsia at almost the same rates. This is partially thought to be due to inequalities in accessing quality prenatal care in lower socioeconomic neighborhoods and the effect of structural racism within healthcare systems. Any woman residing in an area with a lower socioeconomic status, regardless of race or age, is predisposed to developing pregnancy complications like circumvallate placenta if quality prenatal care is not available. Women with significant obstetric histories can also be at higher risk for developing any type of pregnancy complication, including circumvallate placenta, and are recommended to be screened for placental abnormalities within their second trimester of pregnancy. Research Directions The placenta plays a dominant role in being responsible for a variety of complications within pregnancy and labor. Placental pathological studies have significantly contributed to recent obstetric literature. Many studies have examined the clinical significance of patients with circumvallate placenta compared to patients with a normal placenta. They have revealed that incidences of preterm birth, oligohydramnios, placental abruption, low birth weight, and fetal death were present in significantly higher rates than when compared to control patients with normal placentas. Because circumvallate placenta is such a rare condition, it is difficult to gain significant evidence and data.A case study reported in 2020 observed the correlation between circumvallate placenta and the occurrence of obstetric complications such as battledore insertion. Battledore insertion, abnormal insertion of the umbilical cord into the placenta, occurs in about 7% of pregnancies and can also result in many of the same pregnancy complications as circumvallate placenta; intrauterine growth restriction, fetal distress, and fetal death. This abnormal insertion of the umbilical cord into the placenta can result in a loss of adequate blood flow to the developing fetus due to restriction. The fetus is unable to obtain normal amounts of required oxygen and nutrition through the placenta, and this can further cause other severe complications. In the study, a 22-year-old woman at 28 weeks and 2 days of gestation, presented for a routine third trimester screening. She was noted to have had 2 prior miscarriages at 17 and 20 weeks. A previous normal second trimester routine screening at 21 weeks of gestation did not identify any structural abnormalities within the placenta, decreased fetal size, or abnormally-appearing umbilical cord insertion. The patient also did not have any episodes of vaginal bleeding during the current pregnancy.Upon presenting for routine screening at 28 weeks and 2 days of gestation, the patient was not exhibiting any signs of active contractions and a cardiotocography was performed as part of routine screening. Cardiotocography is a diagnostic tool used during the third trimester of pregnancy to observe fetal heart rates and presence of uterine contractions. It can also be used to detect signs of any sort of fetal distress. In interpreting the cardiotocography that the 22-year-old pregnant woman had completed, it was noted that the fetus appeared to be much smaller than expected and was exhibiting concerns of decreased amniotic fluid volume, oligohydramnios, and restricted blood flow through the umbilical cord. Cardiotocographic monitoring also noted decreases in fetal heart rate every 25 minutes without contractions. Fetal motion was present, with the placenta appearing enlarged and spherical.Decreases in the fetus heart rate, in addition to the other findings of the cardiotocography, ultimately prompted physicians to deliver the baby via emergency cesarean section without major complications. The newborn, with normal APGAR scores and umbilical cord arterial pH levels, was admitted to the neonatal intensive care unit. Upon examining the placenta after delivery, it was noted that the placenta demonstrated the appearance of a circumvallate placenta, and also showed evidence of abnormal umbilical cord insertion into the placenta. Postpartum, the mother had a good recovery and the newborn was discharged from the neonatal intensive care unit 105 days post-birth.This case study discussed the association of circumvallate placenta and abnormal battledore cord insertion in producing pregnancy complications. Restriction of umbilical cord blood flow from the placenta to the fetus and placental abnormalities like circumvallate placenta may work in conjunction to generate fetal distress. Decreased levels of oxygenation and nutrient absorption resulted in decelerations of fetal heart rate and the decision to deliver the fetus via cesarean section to prevent fetal death by hypoxia. Routine monitoring of fetal growth and development, placental structure, and placental function are recommended with high-risk pregnancies. In patients diagnosed with circumvallate placenta during pregnancy, monthly fetal growth assessments are also recommended. Patients found to have blood flow restrictions to or from the placenta are recommended to undergo weekly ultrasounds with consistent monitoring of fetal heart rate.In a separate case study reported in 2017, a woman at about 35 weeks of gestation presented with preeclampsia and intrauterine fetal demise, or more commonly known as stillbirth. After delivery of the stillborn fetus, examination of the placenta revealed a circumvallate placenta with battledore insertion of the umbilical cord. It was speculated that the combination of circumvallate placenta and battledore insertion had led to the loss of the fetus prior to delivery, as there was no other discernible cause for the stillbirth. While circumvallate placenta and battledore insertion are individually very rare conditions that can result in multiple pregnancy complications, the coexistence of these abnormalities likely resulted in the loss of the fetus. The diminished blood flow and circulation from the placenta to the fetus, as caused by battledore insertion, in combination with the impaired exchange of nutrients and wastes between mother and fetus, as caused by circumvallate placenta, likely contributed to the preeclampsia and this loss of fetal life. Thus, it is highly recommended that if placental or umbilical cord abnormalities, such as circumvallate placental and battledore insertion, are suspected or detected prior to birth, that the pregnancy should be considered high-risk. High-risk pregnancies significantly benefit from frequent follow-ups using ultransonography to monitor fetal developmental and placental and umbilical cord structure and function.Research directions continue to investigate methods in which circumvallate placenta may be more commonly diagnosed during pregnancy before complications can transpire. Biomarkers such as Sflt/PlGF can be used to predict severe pregnancy complications in high-risk pregnancies. Circumvallate placenta appears to be correlated with reduced placental efficacy due to increased placental thickness and abnormal villi function, affecting the Sflt/PlGF ratio. It is thought that obtaining Sflt/PlGF ratios can be used to determine deficiencies in placental function in cases of placental abnormalities. Future research analyzing the contribution of biomarkers like Sflt/PlGF to predict placental abnormalities would be influential to our understanding of many placental deformities, including circumvallate placenta.Due to the rare occurrences of circumvallate placenta, more extensive research trials are unavailable, resulting in data limitations. Therefore, the clinical importance of circumvallate placenta remains uncertain. See also circummarginate placenta References == External links ==

Brown-Séquard syndrome

Brown-Séquard syndrome (also known as Brown-Séquards hemiplegia, Brown-Séquards paralysis, hemiparaplegic syndrome, hemiplegia et hemiparaplegia spinalis, or spinal hemiparaplegia) is caused by damage to one half of the spinal cord, i.e. hemisection of the spinal cord resulting in paralysis and loss of proprioception on the same (or ipsilateral) side as the injury or lesion, and loss of pain and temperature sensation on the opposite (or contralateral) side as the lesion. It is named after physiologist Charles-Édouard Brown-Séquard, who first described the condition in 1850. Causes Brown-Séquard syndrome may be caused by injury to the spinal cord resulting from a spinal cord tumor, trauma [such as a fall or injury from gunshot or puncture to the cervical or thoracic spine], ischemia (obstruction of a blood vessel), or infectious or inflammatory diseases such as tuberculosis, or multiple sclerosis. In its pure form, it is rarely seen. The most common cause is penetrating trauma such as a gunshot wound or stab wound to the spinal cord. Decompression sickness may also be a cause of Brown-Séquard syndrome.The presentation can be progressive and incomplete. It can advance from a typical Brown-Séquard syndrome to complete paralysis. It is not always permanent and progression or resolution depends on the severity of the original spinal cord injury and the underlying pathology that caused it in the first place. Pathophysiology The hemisection of the cord results in a lesion of each of the three main neural systems: the principal upper motor neuron pathway of the corticospinal tract one or both dorsal columns the spinothalamic tractAs a result of the injury to these three main brain pathways the patient will present with three lesions: The corticospinal lesion produces spastic paralysis on the same side of the body below the level of the lesion (due to loss of moderation by the UMN). At the level of the lesion, there will be flaccid paralysis of the muscles supplied by the nerve of that level (since lower motor neurons are affected at the level of the lesion). The lesion to fasciculus gracilis or fasciculus cuneatus (dorsal column) results in ipsilateral loss of vibration and proprioception (position sense) as well as loss of all sensation of fine touch. The loss of the spinothalamic tract leads to pain and temperature sensation being lost from the contralateral side beginning one or two segments below the lesion.In addition, if the lesion occurs above T1 of the spinal cord it will produce ipsilateral Horners syndrome with involvement of the oculosympathetic pathway. Diagnosis Magnetic resonance imaging (MRI) is the imaging of choice in spinal cord lesions.Brown-Séquard syndrome is an incomplete spinal cord lesion characterized by findings on clinical examination which reflect hemisection of the spinal cord (cutting the spinal cord in half on one or the other side). It is diagnosed by finding motor (muscle) paralysis on the same (ipsilateral) side as the lesion and deficits in pain and temperature sensation on the opposite (contralateral) side. This is called ipsilateral hemiplegia and contralateral pain and temperature sensation deficits. The loss of sensation on the opposite side of the lesion is because the nerve fibers of the spinothalamic tract (which carry information about pain and temperature) crossover once they meet the spinal cord from the peripheries. Classification Any presentation of spinal injury that is an incomplete lesion (hemisection) can be called a partial Brown-Séquard or incomplete Brown-Séquard syndrome.Brown-Séquard syndrome is characterized by loss of motor function (i.e. hemiparaplegia), loss of vibration sense and fine touch, loss of proprioception (position sense), loss of two-point discrimination, and signs of weakness on the ipsilateral (same side) of the spinal injury. This is a result of a lesion affecting the dorsal column-medial lemniscus tract, well localized (deep) touch, conscious proprioception, vibration, pressure and 2-point discrimination, and the corticospinal tract, which carries motor fibers. On the contralateral (opposite side) of the lesion, there will be a loss of pain and temperature sensation and crude touch 1 or 2 segments below the level of the lesion via the Spinothalamic Tract of the Anterolateral System. Bilateral (both sides) ataxia may also occur if the ventral spinocerebellar tract and dorsal spinocerebellar tract are affected.Crude touch, pain and temperature fibers are carried in the spinothalamic tract. These fibers decussate at the level of the spinal cord. Therefore, a hemi-section lesion to the spinal cord will demonstrate loss of these modalities on the contralateral side of the lesion, while preserving them on the ipsilateral side. Upon touching this side, the patient will not be able to localize where they were touched, only that they were touched. This is because fine touch fibers are carried in the dorsal column-medial lemniscus pathway. The fibers in this pathway decussate at the level of the medulla. Therefore, a hemi-section lesion of the spinal cord will demonstrate loss of fine touch on ipsilateral side (preserved on the contralateral side) and crude touch (destruction of the decussated spinothalamic fibers from the contralateral side) on the contralateral side.Pure Brown-Séquard syndrome is associated with the following: Interruption of the lateral corticospinal tracts: Ipsilateral spastic paralysis below the level of the lesion Babinski sign ipsilateral to lesion Abnormal reflexes and Babinski sign may not be present in acute injury Interruption of posterior white column: Ipsilateral loss of tactile discrimination, vibratory, and position sensation below the level of the lesion Interruption of lateral spinothalamic tracts: Contralateral loss of pain and temperature sensation. This usually occurs 2–3 segments below the level of the lesion. Treatment Treatment is directed at the pathology causing the paralysis. If the syndrome is caused by a spinal fracture, this should be identified and treated appropriately. Although steroids may be used to decrease cord swelling and inflammation, the usual therapy for spinal cord injury is expectant. Epidemiology Brown-Séquard syndrome is rare as the trauma would have to be something that damaged the nerve fibres on just one half of the spinal cord. History Charles-Édouard Brown-Séquard studied the anatomy and physiology of the spinal cord. He described this injury after observing spinal cord trauma which happened to farmers while cutting sugar cane in Mauritius. French physician, Paul Loye, attempted to confirm Brown-Séquards observations on the nervous system by experimentation with decapitation of dogs and other animals and recording the extent of each animals movement after decapitation. Notes Sources Egido Herrero JA, Saldanã C, Jiménez A, Vázquez A, Varela de Seijas E, Mata P (1992). "Spontaneous cervical epidural hematoma with Brown-Séquard syndrome and spontaneous resolution. Case report". J Neurosurg Sci. 36 (2): 117–19. PMID 1469473. Ellger T, Schul C, Heindel W, Evers S, Ringelstein EB (June 2006). "Idiopathic spinal cord herniation causing progressive Brown-Séquard syndrome". Clin Neurol Neurosurg. 108 (4): 388–91. doi:10.1016/j.clineuro.2004.07.005. PMID 16483712. S2CID 35644328. Finelli PF, Leopold N, Tarras S (May 1992). "Brown-Sequard syndrome and herniated cervical disc". Spine. 17 (5): 598–600. doi:10.1097/00007632-199205000-00022. PMID 1621163. S2CID 37493662. Hancock JB, Field EM, Gadam R (1997). "Spinal epidural hematoma progressing to Brown-Sequard syndrome: report of a case". J Emerg Med. 15 (3): 309–12. doi:10.1016/S0736-4679(97)00010-3. PMID 9258779. Harris P (November 2005). "Stab wound of the back causing an acute subdural haematoma and a Brown-Sequard neurological syndrome". Spinal Cord. 43 (11): 678–9. doi:10.1038/sj.sc.3101765. PMID 15852056. Henderson SO, Hoffner RJ (1998). "Brown-Sequard syndrome due to isolated blunt trauma". J Emerg Med. 16 (6): 847–50. doi:10.1016/S0736-4679(98)00096-1. PMID 9848698. Hwang W, Ralph J, Marco E, Hemphill JC (June 2003). "Incomplete Brown-Séquard syndrome after methamphetamine injection into the neck". Neurology. 60 (12): 2015–16. doi:10.1212/01.wnl.0000068014.89207.99. PMID 12821761. S2CID 13491137. Kraus JA, Stüper BK, Berlit P (1998). "Multiple sclerosis presenting with a Brown-Séquard syndrome". J. Neurol. Sci. 156 (1): 112–13. doi:10.1016/S0022-510X(98)00016-1. PMID 9559998. S2CID 44403915. Lim E, Wong YS, Lo YL, Lim SH (April 2003). "Traumatic atypical Brown-Sequard syndrome: case report and literature review". Clin Neurol Neurosurg. 105 (2): 143–45. doi:10.1016/S0303-8467(03)00009-X. PMID 12691810. S2CID 37419566. Lipper MH, Goldstein JH, Do HM (August 1998). "Brown-Séquard syndrome of the cervical spinal cord after chiropractic manipulation". AJNR Am J Neuroradiol. 19 (7): 1349–52. PMID 9726481. Mastronardi L, Ruggeri A (January 2004). "Cervical disc herniation producing Brown-Sequard syndrome: case report". Spine. 29 (2): E28–31. doi:10.1097/01.BRS.0000105984.62308.F6. PMID 14722422. S2CID 36231998. Miyake S, Tamaki N, Nagashima T, Kurata H, Eguchi T, Kimura H (February 1998). "Idiopathic spinal cord herniation. Report of two cases and review of the literature". J. Neurosurg. 88 (2): 331–35. doi:10.3171/jns.1998.88.2.0331. PMID 9452246. Rumana CS, Baskin DS (April 1996). "Brown-Sequard syndrome produced by cervical disc herniation: case report and literature review". Surg Neurol. 45 (4): 359–61. doi:10.1016/0090-3019(95)00412-2. PMID 8607086. Stephen AB, Stevens K, Craigen MA, Kerslake RW (October 1997). "Brown-Séquard syndrome due to traumatic brachial plexus root avulsion". Injury. 28 (8): 557–58. doi:10.1016/S0020-1383(97)83474-2. PMID 9616398. External links Case studies of Brown-Séquard syndrome

Thrombotic microangiopathy

Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury. It may be seen in association with thrombocytopenia, anemia, purpura and kidney failure. The classic TMAs are hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Other conditions with TMA include atypical hemolytic uremic syndrome, disseminated intravascular coagulation, scleroderma renal crisis, malignant hypertension, antiphospholipid antibody syndrome, and drug toxicities, e.g. calcineurin inhibitor toxicity. Signs and symptoms The clinical presentation of TMA, although dependent on the type, typically includes: fever, microangiopathic hemolytic anemia (see schistocytes in a blood smear), kidney failure, thrombocytopenia and neurological manifestations. Generally, renal complications are particularly predominant with Shiga-toxin-associated hemolytic uremic syndrome (STx-HUS) and atypical HUS, whereas neurologic complications are more likely with TTP. Individuals with milder forms of TTP may have recurrent symptomatic episodes, including seizures and vision loss. With more threatening cases of TMA, and also as the condition progresses without treatment, multi-organ failure or injury is also possible, as the hyaline thrombi can spread to and affect the brain, kidneys, heart, liver, and other major organs. Cause The specific cause is dependent of the type of TMA that is presented, but the two main pathways that lead to TMA are external triggers of vascular injury, such as viruses, bacterial Shiga toxins or endotoxins, antibodies, and drugs; and congenital predisposing conditions, including decreased levels of tissue factors necessary for the coagulation cascade. Either of these pathways will result in decreased endothelial thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, enhanced vascular shear stress, and abnormal vWF fragmentation. The central and primary event in this progression is injury to the endothelial cells, which reduces the production of prostaglandin and prostacyclin, ultimately resulting in the loss of physiological thromboresistance, or high thrombus formation rate in blood vessels. Leukocyte adhesion to the damaged endothelial wall and abnormal von Willebrand factor (or vWF) release can also contribute to the increase in thrombus formation. More recently, researchers have attributed both TTP and HUS to targeted agents, such as targeted cancer therapies, immunotoxins, and anti-VEGF therapy.Bacterial toxins are the primary cause of one category of thrombotic microangiopathy known as HUS or hemolytic uremic syndrome. HUS can be divided into two main categories: Shiga-toxin-associated HUS (STx-HUS), which normally presents with diarrhea, and atypical HUS. The Shiga-toxin inhibits the binding of eEF-1-dependent binding of aminoacyl tRNA to the 60S subunit of the ribosome, thus inhibiting protein synthesis. The cytotoxicity from the lack of protein damages glomerular endothelial cells by creating voids in the endothelial wall and detaching the basement membrane of the endothelial layer, activating the coagulation cascade. Atypical HUS may be caused by an infection or diarrheal illness or it may be genetically transmitted. This category of TMA encompasses all forms that do not have obvious etiologies. Mutations in three of the proteins in the complement cascade have been identified in patients with atypical HUS. Several chemotherapeutic drugs have also been shown to cause damage to the epithelial layer by reducing the ability for the cells to produce prostacyclin, ultimately resulting in chemotherapy-associated HUS, or C-HUS.The second category of TMAs is TTP thrombotic thrombocytopenic purpura, which can be divided into 3 categories: congenital, idiopathic, and non-idiopathic. Congenital and idiopathic TTP are generally associated with deficiencies in ADAMTS13, a zinc metalloprotease responsible for cleaving Very Large vWF Multimers in order to prevent inappropriate platelet aggregation and thrombosis in the microvasculature. Natural genetic mutations resulting in the deficiency of ADAMTS13 have been found in homozygous and heterozygous pedigrees in Europe. Researchers have identified common pathways and links between TTP and HUS, while other sources express skepticism about their common pathophysiology.The repression of the vascular endothelial growth factor (VEGF) can also cause glomerular TMA (damage to the glomerular microvasculature). It is likely that the absence of VEGF results in the collapse of fenestrations in the glomerular endothelium, thus causing microvascular injury and blockages associated with TMA.Manifestations resembling thrombotic microangiopathy have been reported in clinical trials evaluating high doses of valacyclovir (8000 mg/day) administered for prolonged periods (months to years) for prophylaxis of cytomegalovirus (CMV) infection and disease, particularly in persons with HIV infection. A number of factors may have contributed to the incidence of thrombotic microangiopathy in those trials including profound immunosuppression, underlying diseases (advanced HIV disease, graft-versus-host disease), and other classes of drug, particularly antifungal agents. There were no reports of thrombotic microangiopathy among the 3050 subjects in the four trials evaluating Valacyclovir for suppression of recurrent genital herpes. Although one of the trials was in HIV-infected subjects, the patients did not have advanced HIV disease. The implication is that the occurrence of thrombotic microangiopathy is restricted to severely immunosuppressed persons receiving higher Valacyclovir dosages than are required to control HSV infection. Diagnosis CBC and blood film: decreased platelets and schistocytes PT, aPTT, fibrinogen: normal markers of hemolysis: increased unconjugated bilirubin, increased LDH, decreased haptoglobin negative Coombs test. Creatinine, urea, to follow renal function ADAMSTS-13 gene, activity or inhibitor testing (TTP). Treatment The course of treatment and the success rate is dependent on the type of TMA. Some patients with atypical HUS and TTP have responded to plasma infusions or exchanges, a procedure which replaces proteins necessary for the complement cascade that the patient does not have; however, this is not a permanent solution or treatment, especially for patients with congenital predispositions. Monoclonal antibodies like eculizumab and caplacizumab can assist with atypical hemolytic uremic syndrome and acquired thrombotic thrombocytopenic purpura respectively whilst dexamethasone can help with immune thrombotic thrombocytopenic purpura and low molecular weight heparin can help with disseminated intravascular coagulation. See also Microangiopathy Microangiopathic hemolytic anemia References == External links ==

Joint

A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animals skeletal system into a functional whole. They are constructed to allow for different degrees and types of movement. Some joints, such as the knee, elbow, and shoulder, are self-lubricating, almost frictionless, and are able to withstand compression and maintain heavy loads while still executing smooth and precise movements. Other joints such as sutures between the bones of the skull permit very little movement (only during birth) in order to protect the brain and the sense organs. The connection between a tooth and the jawbone is also called a joint, and is described as a fibrous joint known as a gomphosis. Joints are classified both structurally and functionally. Classification The number of joints depends on if sesamoids are included, age of the human and the definition of joints. However, the number of sesamoids is the same in most people with variations being rare.Joints are mainly classified structurally and functionally. Structural classification is determined by how the bones connect to each other, while functional classification is determined by the degree of movement between the articulating bones. In practice, there is significant overlap between the two types of classifications. Clinical, numerical classification monoarticular – concerning one joint oligoarticular or pauciarticular – concerning 2–4 joints polyarticular – concerning 5 or more joints Structural classification (binding tissue) Structural classification names and divides joints according to the type of binding tissue that connects the bones to each other. There are four structural classifications of joints: fibrous joint – joined by dense regular connective tissue that is rich in collagen fibers cartilaginous joint – joined by cartilage. There are two types: primary cartilaginous joints composed of hyaline cartilage, and secondary cartilaginous joints composed of hyaline cartilage covering the articular surfaces of the involved bones with fibrocartilage connecting them. synovial joint – not directly joined – the bones have a synovial cavity and are united by the dense irregular connective tissue that forms the articular capsule that is normally associated with accessory ligaments. facet joint – joint between two articular processes between two vertebrae. Functional classification (movement) Joints can also be classified functionally according to the type and degree of movement they allow: Joint movements are described with reference to the basic anatomical planes. synarthrosis – permits little or no mobility. Most synarthrosis joints are fibrous joints (e.g., skull sutures). amphiarthrosis – permits slight mobility. Most amphiarthrosis joints are cartilaginous joints (e.g., intervertebral discs). synovial joint (also known as a diarthrosis) – freely movable. Synovial joints can in turn be classified into six groups according to the type of movement they allow: plane joint, ball and socket joint, hinge joint, pivot joint, condyloid joint and saddle joint.Joints can also be classified, according to the number of axes of movement they allow, into nonaxial (gliding, as between the proximal ends of the ulna and radius), monoaxial (uniaxial), biaxial and multiaxial. Another classification is according to the degrees of freedom allowed, and distinguished between joints with one, two or three degrees of freedom. A further classification is according to the number and shapes of the articular surfaces: flat, concave and convex surfaces. Types of articular surfaces include trochlear surfaces. Biomechanical classification Joints can also be classified based on their anatomy or on their biomechanical properties. According to the anatomic classification, joints are subdivided into simple and compound, depending on the number of bones involved, and into complex and combination joints: Simple joint: two articulation surfaces (e.g. shoulder joint, hip joint) Compound joint: three or more articulation surfaces (e.g. radiocarpal joint) Complex joint: two or more articulation surfaces and an articular disc or meniscus (e.g. knee joint) Anatomical The joints may be classified anatomically into the following groups: Joints of hand Elbow joints Wrist joints Axillary joints Sternoclavicular joints Vertebral articulations Temporomandibular joints Sacroiliac joints Hip joints Knee joints Articulations of footUnmyelinated nerve fibers are abundant in joint capsules and ligaments as well as in the outer part of intraarticular menisci. These nerve fibers are responsible for pain perception when a joint is strained. Clinical significance Damaging the cartilage of joints (articular cartilage) or the bones and muscles that stabilize the joints can lead to joint dislocations and osteoarthritis. Swimming is a great way to exercise the joints with minimal damage.A joint disorder is termed arthropathy, and when involving inflammation of one or more joints the disorder is called arthritis. Most joint disorders involve arthritis, but joint damage by external physical trauma is typically not termed arthritis. Arthropathies are called polyarticular (multiarticular) when involving many joints and monoarticular when involving only a single joint. Arthritis is the leading cause of disability in people over the age of 55. There are many different forms of arthritis, each of which has a different cause. The most common form of arthritis, osteoarthritis (also known as degenerative joint disease), occurs following trauma to the joint, following an infection of the joint or simply as a result of aging and the deterioration of articular cartilage. Furthermore, there is emerging evidence that abnormal anatomy may contribute to early development of osteoarthritis. Other forms of arthritis are rheumatoid arthritis and psoriatic arthritis, which are autoimmune diseases in which the body is attacking itself. Septic arthritis is caused by joint infection. Gouty arthritis is caused by deposition of uric acid crystals in the joint that results in subsequent inflammation. Additionally, there is a less common form of gout that is caused by the formation of rhomboidal-shaped crystals of calcium pyrophosphate. This form of gout is known as pseudogout. Temporomandibular joint syndrome (TMJ) involves the jaw joints and can cause facial pain, clicking sounds in the jaw, or limitation of jaw movement, to name a few symptoms. It is caused by psychological tension and misalignment of the jaw (malocclusion), and may be affecting as many as 75 million Americans. History Etymology The English word joint is a past participle of the verb join, and can be read as joined. Joint is derived from Latin iunctus, past participle of the Latin verb iungere, join, unite, connect, attach.The English term articulation is derived from Latin articulatio.Humans have also developed lighter, more fragile joint bones over time due to the decrease in physical activity compared to thousands of years ago. See also Arthrology Cracking joints Kinesiology Ligament Replacement joint References External links Synovial joints Illustrations and Classification

Nipple discharge

Nipple discharge is fluid from the nipple, with or without squeezing the breast. The discharge can be milky, clear, green, purulent, bloody, or faintly yellow. The consistency can be thick, thin, sticky, or watery.Nipple discharge may be normal, such as milk in late pregnancy or after childbirth, and in newborns during the first weeks of life. It may also be normal following squeezing, in women during the reproductive years. It is likely abnormal if it occurs in men, contains blood, is from only one breast, or is associated with a breast lump, swelling, redness or overlying skin changes. Reasons for abnormal discharge include an intraductal papilloma, duct ectasia, blocked milk duct, infected breast (mastitis or breast abscess), breast cancer, certain medications, and conditions that raise prolactin.Milky discharge in a non-pregnant, non-breast feeding women is evaluated differently to other abnormal nipple discharge. Often, the cause can be determined based on symptoms and examination. Blood tests may be done to rule out low thyroid or high prolactin. Other tests may include mammography, breast ultrasound, breast biopsy, or skin biopsy.Treatment depends on the underlying cause. Duct ectasia may be treated with surgical removal of the ducts involved. Infectious causes may require antibiotics or incision and drainage. Nipple discharge is the third most common breast complaint by women, after breast pain and a breast lump. About 3% of breast cancer cases are associated with discharge. Signs and symptoms Nipple discharge is fluid from the nipple, with or without squeezing the breast. The discharge can be milky, clear, green, purulent, bloody, or faintly yellow. The consistency can be thick, thin, sticky, or watery. Causes Nipple discharge can arise from any one or more of the 15 to 20 milk ducts that each breast contains, and its causes can be divided into normal (physiological) and abnormal (pathological). Normal Milky liquid from nipples is normal during the last few weeks of pregnancy, after childbirth and during breastfeeding. Some newborn babies may leak a milky liquid which is usually normal and lasts a couple of weeks.Stimulation of breasts by massage, using a breast pump or after mammography, may induce yellow, milky, or green nipple discharge in many healthy women of reproductive age. Abnormal Spontaneous nipple discharge unrelated to pregnancy or lactation is considered abnormal, but mostly have a non-serious cause. Nipple discharge in men is not normal. Discharge from nipples is also more likely to be abnormal (pathological) if it is crystal clear or blood-stained, is from only one breast, or is associated with a breast lump, swelling, redness or overlying skin changes.A blocked or enlarged milk duct can result in nipple discharge.Intraductal papillomas are non-cancerous lesions and commonest in women age 30 to 50. Divided into central and peripheral papillomas, nipple discharge is more frequently observed when they are central. Up to half of women with intraductal papillomas may present with bloody nipple discharge, but it can also be straw-coloured. They are usually too small to feel and have a rare association with breast cancer.15-20% of people with nipple discharge are found to have duct ectasia. This is usually in perimenopausal and menopausal women, who may have associated pain and retraction of the nipple. A lump may also be present.Ductal carcinoma in situ (DCIS) usually presents with abnormal findings on mammography, but can less frequently present with a lump or nipple discharge in women, whereas in men with DCIS, nipple discharge is the common presentation.Infection in a breast, either mastitis or breast abscess may cause a discharge. Eczema of the nipple may result in a discharge with crusting of the nipple skin.Nipple discharge may be due to breast cancer, particularly if there is an accompanying breast lump. A blood-stained discharge may appear in Pagets disease. Milky Some condition that cause a raised prolactin can result in a milky liquid appearing from nipples. These include endocrine causes such as pituitary and thyroid disease, and some medications. Such medications include: Medication for hypertension: Methyldopa, reserpine, verapamil Gastrointestinal agents: Cimetidine, metoclopramide Hormones: Estrogen, birth control pill Opiates: Codeine, heroin, methadone, morphine Psychotropic drugs: Antipsychotics, monoamine oxidase inhibitors, neuroleptics, selective serotonin reuptake inhibitors, tricyclic antidepressantsSome herbs including anise and fennel have also been implicated as causing leaking of fluid from nipples. Diagnosis The evaluation of milky nipple discharge in a non-pregnant, not breast feeding women is different to the assessment of other abnormal nipple discharge. Often, the cause can be ascertained without performing tests.When blood tests are requested, they usually include thyroid tests and prolactin to rule out hypothyroidism and hyperprolactinemia. Other tests that may be considered include mammography, breast ultrasound, CT scan of the head to rule out a pituitary tumour, breast biopsy, x-ray imaging of breast ducts or skin biopsy.The absence of cancerous cells in samples of nipple discharge does not exclude cancer, hence cytology of the nipple discharge is not usually performed. However, guidance on investigations varies and tests are more likely performed if the discharge is bloody, from one breast, and the woman is age over 50. If the test is performed and malignant cells are found, an underlying cancer is highly likely. Treatment Initially, an evaluation for cancer is indicated. Treatment will depend on the cause found, and may involve changing medication, having a lump removed, applying a cream to treat a skin condition or being given medication to treat the condition causing the discharge. Duct ectasia may be treated with surgical removal of the ducts involved. Infectious causes may require antibiotics and/or incision and drainage. Sometimes, no treatment is required.If no abnormality is found, a surgical duct excision may resolve the symptoms. Treatment also depends on whether single-duct or multiple-duct discharge is present, and whether the symptoms of nipple discharge are distressing to the person. In some cases, there may be no need for any further intervention; in others, microdochectomy or a total duct excision may be appropriate. If the person wishes to conserve the ability to breastfeed and only single-duct discharge is present, then ductoscopy or galactography should be considered in view of performing a localised duct excision. Epidemiology Nipple discharge is the third most common breast complaint by women, after breast pain and a breast lump. 10% of women can notice a nipple discharge when squeezing their breast and more than 50% of women can experience this using a breast pump.Most abnormal nipple discharge is not associated with breast cancer, but 1-5% of breast cancers present with nipple discharge. References == External links ==

Crushed

Crushed may refer to: "Crushed" (Ms. Marvel), a 2022 episode of the American television series Ms. Marvel "Crushed" (Roland Lee Gift song) a 2009 single by Roland Lee Gift "Crushed" (The Suite Life of Zack & Cody episode), an episode of the television show The Suite Life of Zack & Cody "Crushed", a song by Limp Bizkit from the 1999 soundtrack album End of Days "Crushed", a song by Eighteen Visions from the 2004 album Obsession "Crushed", a song by Dala from the 2009 album Everyone Is Someone "Crushed", a song by Parkway Drive from the 2015 album Ire "Crushed", a song by Rosette Sharma See also Crush (disambiguation) Crusher (disambiguation) All pages with titles beginning with Crushed All pages with titles containing Crushed

Therapy

A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different types of therapy. Not all therapies are effective. Many therapies can produce unwanted adverse effects. Medical treatment and therapy are generally considered synonyms. However, in the context of mental health, the term therapy may refer specifically to psychotherapy. History Before the creating of therapy as a formal procedure, people told stories to one another to inform and assist about the world. The term "healing through words" was used over 3,500 years ago in Greek and Egyptian writing. The term psychotherapy was invented in the 19th century, and psychoanalysis was founded by Sigmund Freud under a decade later. Semantic field The words care, therapy, treatment, and intervention overlap in a semantic field, and thus they can be synonymous depending on context. Moving rightward through that order, the connotative level of holism decreases and the level of specificity (to concrete instances) increases. Thus, in health care contexts (where its senses are always noncount), the word care tends to imply a broad idea of everything done to protect or improve someones health (for example, as in the terms preventive care and primary care, which connote ongoing action), although it sometimes implies a narrower idea (for example, in the simplest cases of wound care or postanesthesia care, a few particular steps are sufficient, and the patients interaction with that provider is soon finished). In contrast, the word intervention tends to be specific and concrete, and thus the word is often countable; for example, one instance of cardiac catheterization is one intervention performed, and coronary care (noncount) can require a series of interventions (count). At the extreme, the piling on of such countable interventions amounts to interventionism, a flawed model of care lacking holistic circumspection—merely treating discrete problems (in billable increments) rather than maintaining health. Therapy and treatment, in the middle of the semantic field, can connote either the holism of care or the discreteness of intervention, with context conveying the intent in each use. Accordingly, they can be used in both noncount and count senses (for example, therapy for chronic kidney disease can involve several dialysis treatments per week). The words aceology and iamatology are obscure and obsolete synonyms referring to the study of therapies. The English word therapy comes via Latin therapīa from Greek: θεραπεία and literally means "curing" or "healing". Types of therapies Therapy comes in different forms. These include, cognitive behavioral therapy, dialectical behavior therapy, mindful based cognitive therapy, physical therapy, etc. Therapists are here for use and used daily by many people. Therapist are trained to provide treatment to an individual or group. Therapy was invented in the 1800s and the founder was Franz Mesmer, the "Father of Western Psychotherapy". Sigmund Freud then comes into play and shows us the understanding depth of all the different types included in therapy. Therapy is used in many ways to shape and help reform a person. This type of treatment allows individuals to regain gain goals lost or wanting to accomplish. Many individuals come into therapy looking for ways to cope with issues and to receive an emotional release. For example, healing from trauma, in need of support, emotional issues, and many more. . Allowing yourself to express your thoughts and feelings go a long way in therapy recovery, this is called the therapeutic process. By chronology, priority, or intensity Levels of care Levels of care classify health care into categories of chronology, priority, or intensity, as follows: Emergency care handles medical emergencies and is a first point of contact or intake for less serious problems, which can be referred to other levels of care as appropriate. Intensive care, also called critical care, is care for extremely ill or injured patients. It thus requires high resource intensity, knowledge, and skill, as well as quick decision making. Ambulatory care is care provided on an outpatient basis. Typically patients can walk into and out of the clinic under their own power (hence "ambulatory"), usually on the same day. Home care is care at home, including care from providers (such as physicians, nurses, and home health aides) making house calls, care from caregivers such as family members, and patient self-care. Primary care is meant to be the main kind of care in general, and ideally a medical home that unifies care across referred providers. Secondary care is care provided by medical specialists and other health professionals who generally do not have first contact with patients, for example, cardiologists, urologists and dermatologists. A patient reaches secondary care as a next step from primary care, typically by provider referral although sometimes by patient self-initiative. Tertiary care is specialized consultative care, usually for inpatients and on referral from a primary or secondary health professional, in a facility that has personnel and facilities for advanced medical investigation and treatment, such as a tertiary referral hospital. Follow-up care is additional care during or after convalescence. Aftercare is generally synonymous with follow-up care. End-of-life care is care near the end of ones life. It often includes the following: Palliative care is supportive care, most especially (but not necessarily) near the end of life. Hospice care is palliative care very near the end of life when cure is very unlikely. Its main goal is comfort, both physical and mental. Lines of therapy Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options can often be ranked or prioritized into lines of therapy: first-line therapy, second-line therapy, third-line therapy, and so on. First-line therapy (sometimes referred to as induction therapy, primary therapy, or front-line therapy) is the first therapy that will be tried. Its priority over other options is usually either: (1) formally recommended on the basis of clinical trial evidence for its best-available combination of efficacy, safety, and tolerability or (2) chosen based on the clinical experience of the physician. If a first-line therapy either fails to resolve the issue or produces intolerable side effects, additional (second-line) therapies may be substituted or added to the treatment regimen, followed by third-line therapies, and so on. An example of a context in which the formalization of treatment algorithms and the ranking of lines of therapy is very extensive is chemotherapy regimens. Because of the great difficulty in successfully treating some forms of cancer, one line after another may be tried. In oncology the count of therapy lines may reach 10 or even 20. Often multiple therapies may be tried simultaneously (combination therapy or polytherapy). Thus combination chemotherapy is also called polychemotherapy, whereas chemotherapy with one agent at a time is called single-agent therapy or monotherapy. Adjuvant therapy is therapy given in addition to the primary, main, or initial treatment, but simultaneously (as opposed to second-line therapy). Neoadjuvant therapy is therapy that is begun before the main therapy. Thus one can consider surgical excision of a tumor as the first-line therapy for a certain type and stage of cancer even though radiotherapy is used before it; the radiotherapy is neoadjuvant (chronologically first but not primary in the sense of the main event). Premedication is conceptually not far from this, but the words are not interchangeable; cytotoxic drugs to put a tumor "on the ropes" before surgery delivers the "knockout punch" are called neoadjuvant chemotherapy, not premedication, whereas things like anesthetics or prophylactic antibiotics before dental surgery are called premedication. Step therapy or stepladder therapy is a specific type of prioritization by lines of therapy. It is controversial in American health care because unlike conventional decision-making about what constitutes first-line, second-line, and third-line therapy, which in the U.S. reflects safety and efficacy first and cost only according to the patients wishes, step therapy attempts to mix cost containment by someone other than the patient (third-party payers) into the algorithm. Therapy freedom and the negotiation between individual and group rights are involved. By intent By therapy composition Treatments can be classified according to the method of treatment: By matter by drugs: pharmacotherapy, chemotherapy (also, medical therapy often means specifically pharmacotherapy) by medical devices: implantation cardiac resynchronization therapy by specific molecules: molecular therapy (although most drugs are specific molecules, molecular medicine refers in particular to medicine relying on molecular biology) by specific biomolecular targets: targeted therapy molecular chaperone therapy by chelation: chelation therapy by specific chemical elements: by metals: by heavy metals: by gold: chrysotherapy (aurotherapy) by platinum-containing drugs: platin therapy by biometals by lithium: lithium therapy by potassium: potassium supplementation by magnesium: magnesium supplementation by chromium: chromium supplementation; phonemic neurological hypochromium therapy by copper: copper supplementation by nonmetals: by diatomic oxygen: oxygen therapy, hyperbaric oxygen therapy (hyperbaric medicine) transdermal continuous oxygen therapy by triatomic oxygen (ozone): ozone therapy by fluoride: fluoride therapy by other gases: medical gas therapy by water: hydrotherapy aquatic therapy rehydration therapy oral rehydration therapy water cure (therapy) by biological materials (biogenic substances, biomolecules, biotic materials, natural products), including their synthetic equivalents: biotherapy by whole organisms by viruses: virotherapy by bacteriophages: phage therapy by animal interaction: see animal interaction section by constituents or products of organisms by plant parts or extracts (but many drugs are derived from plants, even when the term phytotherapy is not used) scientific type: phytotherapy traditional (prescientific) type: herbalism by animal parts: quackery involving shark fins, tiger parts, and so on, often driving threat or endangerment of species by genes: gene therapy gene therapy for epilepsy gene therapy for osteoarthritis gene therapy for color blindness gene therapy of the human retina gene therapy in Parkinsons disease by epigenetics: epigenetic therapy by proteins: protein therapy (but many drugs are proteins despite not being called protein therapy) by enzymes: enzyme replacement therapy by hormones: hormone therapy hormonal therapy (oncology) hormone replacement therapy estrogen replacement therapy androgen replacement therapy hormone replacement therapy (menopause) transgender hormone therapy feminizing hormone therapy masculinizing hormone therapy antihormone therapy androgen deprivation therapy by whole cells: cell therapy (cytotherapy) by stem cells: stem cell therapy by immune cells: see immune system products below by immune system products: immunotherapy, host modulatory therapy by immune cells: T-cell vaccination cell transfer therapy autologous immune enhancement therapy TK cell therapy by humoral immune factors: antibody therapy by whole serum: serotherapy, including antiserum therapy by immunoglobulins: immunoglobulin therapy by monoclonal antibodies: monoclonal antibody therapy by urine: urine therapy (some scientific forms; many prescientific or pseudoscientific forms) by food and dietary choices: medical nutrition therapy grape therapy (quackery) by salts (but many drugs are the salts of organic acids, even when drug therapy is not called by names reflecting that) by salts in the air by natural dry salt air: "taking the cure" in desert locales (especially common in prescientific medicine; for example, one 19th-century way to treat tuberculosis) by artificial dry salt air: low-humidity forms of speleotherapy negative air ionization therapy by moist salt air: by natural moist salt air: seaside cure (especially common in prescientific medicine) by artificial moist salt air: water vapor forms of speleotherapy by salts in the water by mineral water: spa cure ("taking the waters") (especially common in prescientific medicine) by seawater: seaside cure (especially common in prescientific medicine) by aroma: aromatherapy by other materials with mechanism of action unknown by occlusion with duct tape: duct tape occlusion therapy By energy by electric energy as electric current: electrotherapy, electroconvulsive therapy Transcranial magnetic stimulation Vagus nerve stimulation by magnetic energy: magnet therapy pulsed electromagnetic field therapy magnetic resonance therapy by electromagnetic radiation (EMR): by light: light therapy (phototherapy) ultraviolet light therapy PUVA therapy photodynamic therapy photothermal therapy cytoluminescent therapy blood irradiation therapy by darkness: dark therapy by lasers: laser therapy low level laser therapy by gamma rays: radiosurgery Gamma Knife radiosurgery stereotactic radiation therapy cobalt therapy by radiation generally: radiation therapy (radiotherapy) intraoperative radiation therapy by EMR particles: particle therapy proton therapy electron therapy intraoperative electron radiation therapy Auger therapy neutron therapy fast neutron therapy neutron capture therapy of cancer by radioisotopes emitting EMR: by nuclear medicine by brachytherapy quackery type: electromagnetic therapy (alternative medicine) by mechanical: manual therapy as massotherapy and therapy by exercise as in physical therapy inversion therapy by sound: by ultrasound: ultrasonic lithotripsy extracorporeal shockwave therapy sonodynamic therapy by music: music therapy by temperature by heat: heat therapy (thermotherapy) by moderately elevated ambient temperatures: hyperthermia therapy by dry warm surroundings: Waon therapy by dry or humid warm surroundings: sauna, including infrared sauna, for sweat therapy by cold: by extreme cold to specific tissue volumes: cryotherapy by ice and compression: cold compression therapy by ambient cold: hypothermia therapy for neonatal encephalopathy by hot and cold alternation: contrast bath therapy By procedure and human interaction Surgery by counseling, such as psychotherapy (see also: list of psychotherapies) systemic therapy by group psychotherapy by cognitive behavioral therapy by cognitive therapy by behaviour therapy by dialectical behavior therapy by cognitive emotional behavioral therapy by cognitive rehabilitation therapy by family therapy by education by psychoeducation by information therapy by speech therapy, physical therapy, occupational therapy, vision therapy, massage therapy, chiropractic or acupuncture by lifestyle modifications, such as avoiding unhealthy food or maintaining a predictable sleep schedule by coaching By animal interaction by pets, assistance animals, or working animals: animal-assisted therapy by horses: equine therapy, hippotherapy by dogs: pet therapy with therapy dogs, including grief therapy dogs by cats: pet therapy with therapy cats by fish: ichthyotherapy (wading with fish), aquarium therapy (watching fish) by maggots: maggot therapy by worms: by internal worms: helminthic therapy by leeches: leech therapy by immersion: animal bath By meditation by mindfulness: mindfulness-based cognitive therapy By reading by bibliotherapy By creativity by expression: expressive therapy by writing: writing therapy journal therapy by play: play therapy by art: art therapy sensory art therapy comic book therapy by gardening: horticultural therapy by dance: dance therapy by drama: drama therapy by recreation: recreational therapy by music: music therapy By sleeping and waking by deep sleep: deep sleep therapy by sleep deprivation: wake therapy See also Biophilia hypothesis Classification of Pharmaco-Therapeutic Referrals Cure Interventionism (medicine) Inverse benefit law List of therapies Greyhound therapy Mature minor doctrine Medicine Medication Nutraceutical Prevention Psychotherapy Treatment as prevention Therapeutic inertia Therapeutic nihilism, the idea that treatment is useless References External links Media related to Therapies at Wikimedia Commons The dictionary definition of therapy at Wiktionary "Chapter Nine of the Book of Medicine Dedicated to Mansur, with the Commentary of Sillanus de Nigris" is a Latin book by Rhazes, from 1483, that is known for its ninth chapter, which is about therapeutics

Follicular lymphoma

Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant histological feature of this cancer.There are several synonymous and obsolete terms for FL such as CB/CC lymphoma (centroblastic and centrocytic lymphoma), nodular lymphoma, Brill-Symmers Disease, and the subtype designation, follicular large-cell lymphoma. In the US and Europe, this disease is the second most common form of non-Hodgkins lymphomas, exceeded only by diffuse large B-cell lymphoma. FL accounts for 10-20% of non-Hodgkins lymphomas with ~15,000 new cases of it being newly diagnosed each year in the US and Europe. Recent studies indicate that FL is similarly prevalent in Japan.FL is a broad and extremely complex clinical entity with a wide range of manifestations which have not yet been fully systematized. It is commonly preceded by a benign precancerous disorder in which abnormal centrocytes and/or centroblasts accumulate in lymphoid tissue. They may then circulate in the blood to cause an asymptomatic condition termed in situ lymphoid neoplasia of the follicular lymphoma type (i.e. ISFL). A small percentage of these cases progress to FL. Most commonly, however, FL presents as a swelling of lymph nodes in the neck, armpits, and/or groin. Less often, it presents as a gastrointestinal tract cancer, a cancer in children involving lymphoid tissues of the head and neck area (e.g. tonsils), or one or more masses in non-lymphoid tissues such as the testes.FL typically has a slow disease course which persists essentially unchanged for years. However, each year 2-3% of FL cases progress to a highly aggressive form often termed stage 3B FL, to an aggressive diffuse large B-cell lymphoma, or to another type of aggressive B-cell cancer. These transformed follicular lymphomas (t-FL) are essentially incurable. However, recent advancements in the treatment of t-FL (e.g. the addition to standard chemotherapy of agents such as rituximab) have improved overall survival times. These newer regimens may also delay the transformation of FL to t-FL. Additional advances in understanding FL may lead to further improvements in treating the disease. Pathophysiology Genomic alterations The serial progressions of in situ FL to FL and FL to t-FL appear to involve the accumulation of increasing numbers of genomic alterations (i.e. chromosome abnormalities and gene mutations) in the formative B-cell precursors to these disorders. At least some of these alterations appear to cause the over-expression or under-expression of the products of genes that regulate these cells susceptibility to develop further genomic alterations, to survive, to proliferate, and/or to spread to other tissues. In consequence, multiple B-cell clones that exhibit increasing genomic alterations and malignant behaviors populate the disorder. No single genomic alteration seems responsible for the development of each of the spectrum of FL disorders. Rather, interactions between multiple genomic alterations appear to underlie this serial progression. In situ follicular lymphoma In situ follicular lymphoma is an accumulation of monoclonal B cells (i.e. cells descendent from a single ancestral cell) in the germinal centers of lymphoid tissue. These cells commonly bear a pathological genomic abnormality, i.e. a translocation between position 32 on the long (i.e. "q") arm of chromosome 14 and position 21 on chromosome 18s q arm. This translocation juxtaposes the B-cell lymphoma 2 (BCL2) gene on chromosome 18 at position q21.33 near to the immunoglobulin heavy chain locus (IGH@) on chromosome 14 at position q21. In consequence, BCL2 overexpresses its product, BCL2 apoptosis regulator (i.e. Bcl2). Bcl2 functions to inhibit programmed cell death thereby prolonging cell survival. The overexpression of Bcl2 in the B-cells of ISFL is thought to be a critical factor in their pathological accumulation and subsequent malignant progression. Small numbers (e.g. 1 in 100,000) of circulating nucleated blood cells bearing this t(14:18)q32:q21) translocation are found in 50-67% of otherwise healthy individuals. The prevalence of this finding increases with age and years of tobacco smoking. Since most individuals with this translocation in their blood cells do not develop ISFL, the t(14:18)(q32:q21) translocation, while prolonging cell survival, must be just one step in the development of ISFN. This translocation is proposed to occur during the early development of immature bone marrow B-cells (i.e. pre-B-cells/pro-B-cells) after which these cells circulate freely and in rare cases accumulate and mature to centrocytes and/or centroblasts in the germinal centers of lymphoid follicles to form ISFL. The mechanism favoring this localization and further accumulation is unclear.Individuals with ISFL progress to FL at a rate of 2-3%/year for at least the first 10 years following diagnosis. This progression likely involves the acquisition of genomic aberrations besides the t(14:18)q32:q21) translocation in the ISFL B-cells. Suspect mutations include those in the following genes: 1) EZH2 (encodes polycomb repressive complex 2 family protein which is involved in maintaining the transcriptional repressive state of various genes and is found in up to 27% of FL cases); 2) CREBBP (encodes CREB-binding protein which contributes to the activation of various genes); 3) TNFSF14 (encodes tumor necrosis factor superfamily member 14, a member of the tumor necrosis factor superfamily which may function as a co-stimulatory factor for the activation of lymphoid cells); and 4) KMT2D (encodes histone-lysine N-methyltransferase 2D, a histone methyltransferase which regulates the expression of various genes). ISFL may also acquire numerous copy-number variations (i.e. duplications and deletions of a portion of a chromosome along with any of the genes contained therein) that may contribute to FL. In all cases, the number of genetic abnormalities acquired in the B-cells of ISFL are much less than those in FL. Follicular lymphoma The genomic alterations found in FL include 1) the t(14:18)(q32:q21.3) translocation (85-90% of cases); 2) 1p36 deletions (i.e. deletions in the q arm of chromosome 1 at position 36, [60-70% of cases]) that lead to lose of TNFAIP3 (encodes tumor necrosis factor, alpha-induced protein 3 which inhibits the activation of NF-κB, blocks cell death due to apoptosis, and regulates lymphocyte-based immune responses through its ubiquitin ligase activity); 3) mutations in PRDM1 (encodes the PR domain zinc finger protein which promotes the maturation and proliferation of B-cells); and 4) the same mutations seen in ISFL including KMT2D (85-90% of cases), CREEBP (40-65% of cases), BCL2 (40-65% of cases), and EZH2 (20-30% of cases) as well as other mutations such as those in the histone-modifying gene HIST1H1E (20-30% of cases), the RRAGC gene (~17% of cases) which regulates cell growth, survival, death, and proliferation, and, in ≤15% of cases several other genes including MEF2B, STAT6, EP300, ARID1A, SLC22A2, CARD11, FOXO1, GNA12, B2M (i.e. the gene for beta-2 microglobulin), and SGK1. Except for the t(14:18)(q32:q21.3) translocation and EZH2 mutations which lead to gains in the expression and function, respectively, of their products, the genetic alterations generally lead to a loss in the production or function of the cited genes products. However, the exact roles, if any, of these genomic abnormalities in promoting the progression of ISFL to FL are unclear. Transformed follicular lymphoma The transformation of FL to a more aggressive state or other type of aggressive lymphoma is associated with: 1) primarily gene-activating mutations in CREEBP, KMT2D, STAT6, CARD11 (encoding a guanylate kinase which interacts with BCL10 and activates NF-κB to regulate cell survival); 2) changes in the expression of diverse genes; 3) the overproduction of various cell-activating cytokines and CD79B (encoding the Ig-beta protein component of the B-cell receptor); 4) gene-inactivating mutations in TNFAIP3, CD58 (encoding the cell adhesion molecule, lymphocyte function-associated antigen 3, that is involved in activating T-cells), CDKN2A (encoding p16INK4a and p14arf tumor suppressor proteins) or CDKN2B (encoding cyclin dependent kinase inhibitor 2B multiple tumor suppressor 2) (inactivation of either CDKN2 gene causes genome instability, i.e. increased frequency of other gene mutations), and TNFRSF4 (encoding one type of tumor necrosis factor receptor); and 5) gene-activating or -inactivating mutations in, or other causes for the under- or over-expression of, c-MYC ((encoding the c-Myc proto-oncogene transcription factor that regulates the expression of diverse genes many of which promote cell proliferation). Tumor environment The non-neoplastic immune and stromal cells as well as the extracellular matrix in tissues may enable neoplastic follicular cells to survive, proliferate, and avoid surveillance by the immune system. For example, laboratory studies show that: 1) follicular dendritic cells, fibroblastic reticular cells, and T helper cells provide growth and survival signals to neoplastic follicular B-cells; 2) neoplastic follicular B-cells recruit regulatory T cells that act to suppress immune responses to them; 3) the cytotoxic T-cells which normally kill neoplastic cells become dysfunctional in the presence of neoplastic follicular cells that are embedded in this multicellular environment; and 4) bone marrow stromal cells directly support the growth of neoplastic follicular cells. Reduced levels of immune-infiltration has been shown to be strongly associated with early progression of disease. Presentation and course In situ follicular lymphoma FL is commonly preceded by but uncommonly progresses to ISFL, an asymptomatic disorder that usually is discovered in tissues which are biopsied for other reasons. FL lymphoma may be diagnosed in the uncommon cases in which individuals with ISFL are found to have FL on follow-up examinations. Similarly, individuals with >1 in 10,000 circulating lymphocytes containing the t(14:18)q32:q21) translocation are at increased but still small risk of developing FL and being diagnosed as having FL on follow up examinations. Follicular lymphoma FL commonly presents as an otherwise asymptomatic enlargement of lymph nodes in the neck, armpit, groin, femoral canal, or other sites in individuals (median age 65) without a known history of ISFL or abnormal numbers of circulating t(14:18)q32:q21-conatianing lymphocytes. These enlargements may have been present for months to years and during this time waxed and waned in size. Less commonly, FL presents as extra-nodal masses in the skin, thyroid gland, salivary gland, breast, testicles. spleen, liver, and/or lung. Regardless of the type of presentation, FL is usually (~80% of cases) at an advanced stage at diagnosis as indicated by involvement of the bone marrow (50% to 70% of cases), multiple lymph nodes in different parts of the body, and/or other tissues. A minority (<33%) of FL patients present with B symptoms, i.e. recurrent unexplained fevers, recurrent night sweats, and/or weight loss ≥10% in the past 6 months. Generally, the disease has an indolent and prolonged course with a median life expectancy of 15–20 years: a large percentage of patients die from other causes than their FL disease. However, each year, including the early years after diagnosis, some 2-3% of FL cases transform to t-FL; Median survival has been ~4.5 years after the onset of this transformation.There are less common subtypes of FL that differ not only in their presentation but also in their histopathology, genetic abnormalities, and course. These subtypes, which are now (i.e. primary gastrointestinal tract FL) or may in the future (pediatric-type FL) be considered distinctive diseases, are: Duodenal-type follicular lymphoma Duodenal-type follicular lymphoma (DFL) was initially considered to be a type of Primary gastrointestinal tract (GI tract) follicular lymphoma (PGTFL), i.e. a follicular lymphoma in which GI tract lesions were prominent parts of the disease. However, a subset of PGTFL cases had lesions that were localized to the duodenum and other parts of the small intestine usually without involving other parts of the GI tract or tissues outside of the GI tract. This contrasts with the other cases of PGTFL which were systemic diseases involving a wide range of GI tract and non-GI tract tissues. Consequently, the World Health Organization (2017) removed the localized disease from the primary gastrointestinal tract follicular lymphoma category, reclassified it as a distinct disease entity, and termed it duodenal-type follicular lymphoma. DFL is most often an asymptomatic disease that is diagnosed on endoscopic examination of the GI tract conducted for other reasons. Less commonly, it presents with vague abdominal symptoms. In one review of former studies, the lesions in 85% of primary duodenal follicular lymphoma were located not only in the duodenum but also other sites in the intestine (i.e. jejunum and/or ileum), with rare cases having lesions in the rectum or cecum PDF is an indolent disease that may spontaneously remit and relapse but only rarely progresses to a more aggressive form. A watch-and-wait strategy has been a generally recommended method for the initial treatment of the disease. Primary gastrointestinal tract follicular lymphoma PGTFL is a follicular lymphoma (which as currently defined excludes cases of duodenal-type follicular lymphoma) that has a prominent component of GI tract involvement. The disease may present with signs and symptoms typical of the common type of follicular lymphoma. For example, enlargement of lymph nodes in the neck, armpit, groin, femoral canal, and/or other areas, and/or signs and symptoms of GI tract disease due to lesions in the stomach, small intestine, large intestine or rectum may be seen. These signs and symptoms may include abdominal pain, bowel obstruction, persistent nausea and vomiting, hematochezia (i.e. passage of fresh blood usually on feces through the rectum), or melena (i.e. passage of tarry feces containing blood that has been digested in the stomach or upper intestine). PGTFL is generally treated like cases of common follicular lymphoma: depending on the severity of the disease and its symptoms, patients are treated with watchful waiting, surgery, chemotherapy, radiation, immunotherapy plus radiotherapy, or combinations of these modalities. Predominantly diffuse follicular lymphoma with 1p36 deletion Predominantly diffuse follicular lymphoma with 1p36 deletion is a rare subtype of FL in which involved lymph nodes show infiltrations of centrocytes and centoblasts that generally do not form the nodular, swirling patterns characteristic of most types of FL. In addition, these cells lack the t(14:18)(q32:q21.3) translocation commonly found in other FL types but, similar to many FL cases, have a deletion in the terminal part of the short (i.e. "p") arm of chromosome 1 that encodes the TNFRSF14 gene (see pathophysiology section). Predominantly diffuse follicular lymphoma with 1p36 deletion usually presents with bulky enlargements of inguinal (i.e. groin) lymph nodes but may present with enlargements of the axillary (i.e. armpit) or cervical (i.e., neck) lymph nodes. In rare cases, there may be involvement of the bone marrow. In spite of the evidence of bulky and disseminated disease, predominantly diffuse follicular lymphoma with 1p36 deletion appears to be an indolent disorder that may require long-term observation rather than overtreatment. Pediatric-type follicular lymphoma Pediatric-type follicular lymphoma (PTFL) was initially reported to occur in children ages 1–17 years old (median age ~13-14) but more recently has been reported to occur in adults. The disorder was recently defined by the World Health Organization (2016) as a distinct entity that occurs mostly in males and involves swollen lymph nodes in the head (including tonsils and adenoids), neck, or, rarely, axillary, or inguinal areas, or non-lymphoid tissues. Currently, however, patients who had exhibited or are exhibiting involvement of areas or tissues outside of the head, neck, armpit, or groin areas are now regarded as far more likely to have a newly and provisionally defined disease, large B-cell lymphoma with IRF4 rearrangement.The lesions in PTFL consists of infiltrates containing rapidly proliferating centrocytes and centroblasts that lack the t(14:18)(q32:q21.3) translocation but nonetheless often overexpress the BCL2 gene. These cells may show a loss of heterozygosity at 1p36 (20-50% of cases) that results in decreased expression of the TNFRSF14 gene (see Pathophysiology section) as well as mutations in the IRF8 (10-50% of cases), which contributes to the development and function of B cells, and the MAP2K1 gene (10-40% of cases), which regulates activation of the ERK cell signaling pathway. More than 2 dozen other genes have been reported to be mutated in rare cases of PTFL but in general the genetic abnormalities found in this disorder are fewer and less complex than those in other types of FL. PTFL has an indolent, relapsing and remitting course with a 5-year survival rate of >95%. Patients diagnosed with PTFL have been treated with chemotherapy, surgery, and combinations of these treatments. In general, these patients did well (100% survival with <5% of cases relapsing regardless of treatment modality). More recently, 36 patients have been treated with surgical resection alone followed by observation; all these patients survived with only one having a relapse. Thus, PTFL appears to be a highly indolent type of FL in which multiple studies have reported overall and progression-free survival rates of 100% and >90%, respectively, for >2 years and an estimated probability of 5-year event-free survival rate of ~96%. The therapeutic regimens versus follow-up observations that best treat this disorder in children, adolescents, and adults (adults may require different treatments than children and adolescents) requires further study. Primary follicular lymphoma of the testis Primary follicular lymphoma of the testis (PFLT), also termed testicular follicular lymphoma, was classified as a distinct form of FL by the World Health Organization in 2016. It is an extremely rare disease that has been recognized as occurring primarily in children and adolescents but also has been reported in 5 adults. PFLT differs from cases of typical follicular lymphoma that involve the testis in that it more often occurs in children and adolescents; involves malignant B-cells that do have the t(14:18)q32:q21) translocation; and presents with disease that is strictly limited to the testis. While similar to pediatric-type follicular lymphoma in not involving cells that bear the t(14:18)q32:q21) translocation, PFLT differs from the former disease in that it is limited to the testis and involves malignant cells that do not express Bcl2. PFTL is an extremely indolent disease which is manifested by lesions that exhibit a typical FL histology or, more commonly, a mixed FL-diffuse large cell lymphoma histology. It usually involves a 2-4 centimeter lesion in a single testicle. Patients have been treated with removal of the involved testes followed by various standard anti-lymphoma chemotherapy regimens to attain excellent results, i.e. 100% completed remissions with no recurrence of disease in 15 child and adolescent patients observed for 4–96 months. No cases of primary follicular lymphoma of the testis have been reported to progress to t-FL. Surgery followed by less strenuous or even no chemotherapy may prove to be the optimal treatment for this disease. Transformed follicular lymphoma FL progresses at a rate of 2-3% per year for at least the first 10 years after diagnosis to a more aggressive form, principally diffuse large B-cell lymphoma (~93% of cases) or Burkitt-like lymphoma (~7% of cases) or in rare cases exhibit the histology resembling precursor B-cell lymphoblastic leukemia, plasmablastic lymphoma, the high grade subtype of B-cell lymphoma, Hodgkin lymphoma of the B-cell type, chronic lymphocytic leukemia/small cell lymphcytic lymphoma, or histiocytic sarcoma. t-FL is almost always diagnosed in patients being followed for FL. These FL patients present with the: fast growth of lymph nodes; formation of extra-nodal lesions in extra-nodal sites such as the central nervous system, liver or bone; the onset of B-symptoms (i.e. fever, night sweats, weight loss); development of hypercalcemia (i.e. high serum levels of calcium); and/or sudden rises in serum levels of the enzyme lactate dehydrogenase. A minority of t-FL patients present without a history of FL. These patients generally present with advanced, bulky disease that may be accompanied by extra-nodal lesions and B-symptoms. Typically, all the various forms of t-FL are aggressive, rapidly progressive diseases with overall media survival times in treated patients of ~4.5 years. The transformation of FL to DLBCL is in over 70% of cases associated with the gain of MYC activity by genetic or non-genetic mechanisms. Diagnosis The diagnosis of FL depends on examining involved tissues for histological, immunological, and chromosomal abnormalities that are indicative of the disease. FL usually involves enlarged lymph nodes populated by abnormal follicles (see adjacent picture) that when examined histologically contain a mixture of centrocytes or centroblast surrounded by non-malignant cells, mostly T-cells. The centrocytes, which typically outnumber centroblasts, are small to medium-sized B-cell lymphocytes that characteristically exhibit cleaved nuclei; the centropblasts are larger B-cell lymphocytes without cleaved nuclei. Rare cases of FL may show lesions that contain tissue infiltrations dominated by B-cells with features of precursor (i.e. "blast") cells, monocytes, or malignant mantle cells such as those found in mantle cell lymphoma. Immunochemical analyses reveal that these cells generally express B-cell surface markers including the CD10 (60% of cases), CD20, CD19, CD22, and CD79 but not CD5, CD11c, or CD23 cell surface proteins; genomic analyses reveal that these cells contain t(14:18)(q32:q21.3) translocation (85-90% of cases), 1p36 deletions (60-70% of cases), and with far less frequency the other genomic abnormalities listed in the above sections on Pathophysiology and Presentation and course. None of these protein markers or genomic abnormalities are diagnostic for FL, e.g. the t(14:18)(q32:q21.3) translocation is found in 30% of diffuse large B-cell lymphoma and in a small number of reactive benign lymph nodes. Rather, the diagnosis is made by a combination of histological, immunological, and genomic abnormalities. According to World Health Organization (WHO) criteria, differences in the microscopically determined morphology of these tissues can be used to diagnose and categorized FL into the following 3 Grades with grade 3 having A and B subtypes: Grade 1: follicles have <5 centroblasts per high-power field (hpf). Grade 2: follicles have 6 to 15 centroblasts per hpf. Grade 3: follicles have >15 centroblasts per hpf. Grade 3A: Grade 3 in which the follicles contain predominantly centrocytes. Grade 3B: Grade 3 in which the follicles consist almost entirely of centroblasts.Grades 1 and 2 are regarded as low grade FL; Grade 3A is usually also regarded as low grade FL although some studies have regarded it as high grade FL; and Grade 3B is regarded as a highly aggressive FL in the t-FL category.In addition to grade 3B disease, histologic examinations may reveal other evidence of t-FL such as histologic findings consistent with FL and diffuse large cell lymphoma in the same tissue (referred to as composite lymphomas) or in separate tissues (referred to as (discordant lymphomas) or histologic findings similar to those found in Burkitt lymphoma, precursor B-cell lymphoblastic leukemia, plasmablastic lymphoma, the high grade subtype of B-cell lymphoma, Hodgkin lymphoma of the B-cell type, chronic lymphocytic leukemia/small cell lymphocytic lymphoma, or histiocytic sarcoma. Other findings indicating the presence of this transformation include rapid growth in size of lymph nodes, recently acquired or new B symptoms, recent development of FL lesions in non-nodal tissue, rapid rises in serum lactate dehydrogenase levels, and the presence of high levels of serum calcium. Differential diagnosis FL may be confused with marginal zone B-cell lymphoma, mantle cell lymphoma, and the small lymphocytic lymphoma variant of chronic lymphocytic leukemia. The malignant cells in marginal zone B-cell lymphoma may form follicular structures but commonly proliferate in the marginal zone rather than germinal center of lymphoid tissues. These malignant cells often show features of monocytes or plasma cells. Mantle cell lymphomas show monotonous, medium-sized lymphocytes, monocytes, and atrophied germinal centers; unlike FL, the malignant lymphocytes in this disease are positive for Cyclin D1 by immunohistochemistry staining. Small lymphocytic lymphomas are composed of nodular structures with small- to medium-sized malignant cells surrounding immature lymphocytes and immunoblasts. The malignant cells in this disease, unlike FL, stain positive for CD5 and CD23. Treatment and prognosis FL is typically a slowly growing lymphoma with an overall median life expectancy for treated patients of 10–15 years with many cases of it waxing and waning in the size of their lesions and rare cases of it remitting spontaneously. These considerations favor the use of observation over intervention in patients whose particular form of FL has a favorable prognosis or who are intolerant to aggressive treatments. However, most cases of FL have a less favorable prognosis at some stage of their disease and will therefore require intervention. There is little consensus regarding the guidelines to be used to define the prognosis and treatment for FL at its presentation or during its course.. Currently used indicators for this include the diseases: 1) histology; 2) subtype; 3) predicted indolence and potential for transformation; and 4) extent of disease as measured by clinical examinations,

Follicular lymphoma

bone marrow biopsy to determine bone marrow involvement, and PET/CT imaging of the chest, abdomen, pelvis, and any areas outside of these regions if physical examination suggests involvement. Some suggested guidelines using these parameters to indicate the prognosis and need for treatment in FL include: The WHO criteria using histological grade (see previous section): Patients with Grades 1, 2, and 3A disease are predicted to have the same low risk prognosis that is seen in cases of typical FL while patients with grade 3B disease are predicted to have the high risk prognosis typical of t-FL. The Follicular Lymphoma International Prognostic Index (FLIPI): FLIPI uses the following criteria: age ≥60 years; Ann Arbor disease stage III (i.e. lesions located both above and below the thoracic diaphragm) or IV (i.e. disseminated lesions involving one or more non-lymphatic organs); blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; and involvement of >4 lymph nodes. Patients positive for 0–1, 2, or ≥3 of these factors are classified as in low, intermediate, and high risk group, respectively, and after treatment with regimens that include rituximab have 2 year predicted progression free survivals of 84, 72, and 65%, respectively, and overall survivals of 98, 94, and 87%, respectively. The FLIP2 index. This modification of FLIP1 uses age ≥60; blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; serum beta-2 microglobulin level above normal; ≥1 lymph node with a diameter >6 centimeters; and bone marrow involvement. The predicted percentage of therapy-treated patients with progression free survival at 5 years for individuals positive for 0, 1–2, and ≥3 of these factors are 80, 51, and 19%, respectively. CT/PET imaging: This method measures total body tumor volume as detected by tissue uptake of radioactive fludeoxyglucose (F18). Progression free and overall survival at 5 years for patients with estimated tumor volumes above versus below 510 cubic centimeters are reported to be 32.7 and 84.8% versus 65.1 and 94.7%, respectively. Lugano staging: this method classifies Stage I disease as involving a single lymphatic region or extra-lymphatic site; Stage II disease as involving ≥2 lymphatic sites or 1 lymphatic site plus 1 extralympatic site with all lesions being on the same side of the diaphragm; Stage III disease as involving ≥2 lymphatic regions that are on opposite sides of the diaphragm; and Stage IV disease as disseminated lesions that are found to be in ≥1 non-lymphatic organs. Response-based prognosis: FL patients whose disease progresses within 24 months of initiating treatment with chemotherapy and immunotherapy versus patients whose disease does not progress within 24 months are predicted to have 5 year survival rates of 50-74% versus ~90%, respectively.The prognosis and treatment for the specific presentations of typical FL cases (see above sections for the prognoses and treatment recommendations for primary gastrointestinal tract FL, predominantly diffuse FL with 1p36 deletion, pediatric-type FL, and primary FL of the testis) that are in common use are as follows: In situ follicular lymphoma ISFL is a benign condition that may be reevaluated periodically to detect the rare cases of it which progress to FL; otherwise ISFL is not treated. Localized follicular lymphoma In 10-20% of cases, FL appears limited to single radiation field, does not involve the bone marrow, and is therefore regarded as localized early-stage FL. In these cases, which are sometimes classified as Ann Arbor stage I (i.e. disease limited to a single restricted region) or stage II (i.e. disease restricted to two sites that are on the same side of the diaphragm), radiation therapy achieves 10 year overall survival rates of 60-80% and median overall survival times of 19 years. It seems likely that many of the relapses in these cases are due to undetected disease outside of the radiation field at the time of radiation treatment. The use of PET/CT imaging is strongly recommended to insure that the FL is localized. In any case, the excellent results achieved with radiation therapy strongly support its use in localized disease. The use of an immunotherapeutic agent such as Rituximab alone or in combination with a chemotherapeutic regimen such as CVP (i.e. cyclophosphamide, vincristine, prednisone and rituximab) in cases of localized, early-stage disease may be appropriate choices for some of these early-stage patients. However, the latter approach is recommended for cases of localized disease in which the disease extends beyond a single field: 56% of patients treated in this manner had progression-free survival at 10 years while patients treated with other regimens had progression free survivals of 41%. Nonetheless, overall survival did not differ between the two groups. Asymptomatic follicular lymphoma Patients with asymptomatic but not localized low grade FL, gastrointestinal tract FL, and pediatric-type follicular lymphoma have been served by careful follow-up without therapeutic intervention. Even high grade, aggressive, relapsed, or transformed FL may also be served with observation in patients who are asymptomatic. Findings in asymptomatic patients who have been recommended as triggers for starting treatment include one or more of the following: tumor size ≥7 cm in diameter; involvement of ≥3 nodes in 3 distinct areas, each of which is ≥3 cm in diameter; organ compression; presence of ascites or pleural effusion (i.e. build-up of fluid in the abdominal or pleural cavities); poor performance status due to the disease; elevated levels of serum lactose dehydrogenase or beta-2 microglobulin; presence of localized bone lesions; kidney involvement; reduced levels of circulating blood platelets or any of the various types of white blood cells; onset of significant pruritus (i.e. itching sensation) or other B symptoms; and enlargement (i.e. ≥50% increase in size over a period of at least 6 months) of lymph nodes, spleen, or other follicular lymphoma-infiltrated organs or tissues. Symptomatic follicular lymphoma Symptomatic FL requires treatments directed at relieving symptoms by reducing the load of tumor cells. Various chemotherapeutic regimens have been used for this including combinations of alkylating antineoplastic agents, nucleoside analogues, and/or anthracyclines. Two commonly used chemotherapeutic regimens are CVP (see Localized FL section) and CHOP (i.e. CVP plus the anthracycline adriamycin). Newer agents used to treat FL include monoclonal antibodies such as rituximab, obinutuzumab, galiximab, inotuzumab ozogamicin, or epratuzumab and immunomodulators such as lenalidomide and interferon. The latter medications have been used in combination or alone to treat symptomatic FL. Most such regimens add rituximab (a monoclonal antibody which binds and thereby kills the CD20 cell surface protein on B cells) with CVP or CHOP regimens (termed R-CVP and R-CHOP regimens). The R-CHOP regimen appears superior to the R-CVP regimen with, for example, one study finding 8-year progression-free survival rates of 57% versus 46% for the two respective regimens. More recently, FL patients have been treated with other regimens including: 1) rituximab combined with the chemotherapeutic alkylating agent bendamustine; 2) rituximab combined with the chemotherapeutic agent fludarabine and the inhibitor of Type II topoisomerase, mitoxantrone; and 3) rituximab combined with another immunotherapeutic agent such as galiximab, epratuzumab (monoclonal antibodies directed respectively against the CD80 or CD22 cell surface proteins on immune cells including B cells), or the immunomodulating medication, lenalidomide. While it is too soon to judge the long-term results of the latter regimens, the regimens have shown similar results when analyzed based on poor treatment responses (~10-20% poor responses). Bendamustine with rituximab may be preferable to R-CHOP or R-CVP for treating low-grade (i.e. Grades 1, 2, and possibly 3A) FL; R-CHOP may be preferred in FL that has high-risk characteristics (e.g. high levels of Beta-2 macroglobulin or bone marrow involvement). The combination of lenalidomide with rituximab has shown good potential in treating indolent cases of FL.Studies indicate that maintenance therapy with rituximab following successful induction therapy prolongs progression-free survival; for example one study found progression-free survival after 6 years of treatment was 59.2% in patients treated with rituximab maintenance and 42.7% without this maintenance; however, overall survival at 6 years was similar in the two groups, 87.4% and 88.7%, respectively. Another study found that prolonged maintenance with rituximab did not have any benefits over an eight-month maintenance period. Finally, surgery and radiation are additional therapies that can be used to relieve symptoms caused by bulky t-FL disease or to treat lesions in patients who cannot withstand other types of treatment. Transformed follicular lymphoma Early studies on treating t-FL with various purely chemotherapy regimens gave poor results with median overall survival times of 1–2 years. However, the addition of rituximab to the regimens such as CVP and CHOP as part of induction and maintenance therapies (i.e. R-CVP and R-CHOP) greatly improved overall 5 year survival to rates of 73%. The R-CHOP regimen is a good option for treating such cases. However, these regimens need not be started in people with FL who are asymptomatic and have low tumor burdens: the outcomes in such patients show no difference between early versus delayed treatment. Some recent studies found that the use of rituximab in combination with bendamustine (i.e. the RB regimen) provided better results than R-CHOP: progression-free survival times in one study were 69.5 months for RB and 31.2 months for R-CHOP. Similar results were obtained when RB was compared to R-CVP. These studies also found no overall survival time benefit between the RB and R-CHOP regimens. Other recently examined regimens include 1) the use of obinutuzumab instead of rituximab in the R-CHOP and R-CVP regiments to attain progression-free survival rates at 3 years of 80% for the obinutuzumab-chemotherapy regimen versus 73% for the rituximab-chemotherapy regimen and 2) the combination of rituximab with lenalidomide (no chemotherapy agent) versus various chemotherapy plus immunotherapy (principally rituximab) to achieve similar complete remission and 3 year progression-free survival rates but with rituximab plus lenalidomide causing less toxicity (i.e. severe neutropenia). Many of these studies did use rituximab maintenance therapy after induction therapy. Prevention Several studies, while not conclusive, suggest that the early treatment of low risk FL reduces the incidence of the disease progressing to t-FL. The treatments used in these studies include chemotherapy, radiation therapy, and immunotherapy combinations plus rituximab maintenance therapy. Relapsed follicular lymphoma Patients who relapse after initial therapy for FL may be followed closely without therapy if asymptomatic. When treatment is required, patients may be treated with the initial treatment regimen when such treatment led to a remission that lasted for at least one year; otherwise an alternative regimen is used. The regimens commonly used in relapsed lymphoma include R-CHOP, R-CVP, RFM (i.e. rituximab, fludarabine, and mitoxantrone), and RB (Bendamustine plus rituximab). Patients who have early treatment failure (e.g. within 1–2 years of initial treatment) or multiple relapses have also been treated with either autologous (i.e. stem cells taken from patient) or allogeneic (i.e. stem cells taken from a donor) stem cell bone marrow transplantation. While studies are inconclusive, autologous stem cell bone marrow transplantation appears to prolong survival in early treatment failure patients who are healthy enough to withstand this therapy. Unfit patients may benefit from initial treatment with obinutuzumab plus bendamustine followed by maintenance treatment with obinutuzumab (if they have not been treated previously with obinutuzumab).Other mostly experimental treatments currently under study in patients with multiple treatment failures include: 1) Phosphoinositide 3-kinase inhibitors such as copanlisib, duvelisib, and idelalisib which block the phosphoinositide 3-kinase signaling pathway that promotes the survival, proliferation, and other potentially malignant behaviors of cells; 2) infusion of tisagenlecleucel chimeric antigen receptor T cells (i.e. CAR T cells) (i.e. T cells that have been isolated from patients, engineered to express a receptor for the CD19 protein on, and thereby kill, T cells, and then infused back into the donor patient); 3) Bruons tyrosine kinase inhibitor, ibrutinib, to block the B-cell maturating actions of this kianase; 4) BCL inhibitor venetoclax to block Bcl2s action in promoting B-cell survival and proliferation; 5) histone deacetylase inhibitors abexinostat and tazemetostat to modify the expression of various genes; and 6) Checkpoint inhibitors nivolumab, pidilizumab, and pembrolizumab to promote the immune systems ability to suppress cancer cell growth. In preliminary studies on FL patients who were known or thought to be refractor to more conventional therapies these drugs, when combined with more conventional drugs, particularly rituximab, produced promising results. Phosphoionsitide 3-kinase inhibitors produced overall response rates of 10–12.5 months in 42-59%; tisagenlecleuce cells produced an overall progression-free response rate of 70% after a follow-up of 28 months; phosphoinositide 3-kinase inhibitors produced overall response rates of ~40% and complete response rates of 1-20%; Brutons tyrosine kinase inhibitor produced overall and complete response rates of 38% and 18%, respectively; the Bcl inhibitor produce overall and complete response rates of 33% and 14%, respectively; histone deacetylase inhibitors produce overall response rates of 35%-71%; and checkpoint inhibitors produce overall response rates of 40%-80% and complete response rates of 10-60%. See also List of hematologic conditions large-cell lymphoma In situ follicular lymphoma References External links Follicular large cell lymphoma entry in the public domain NCI Dictionary of Cancer Terms

Gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior is driven by mutations in the KIT gene (85%), PDGFRA gene (10%), or BRAF kinase (rare). 95% of GISTs stain positively for KIT (CD117). Most (66%) occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract. Classification GIST was introduced as a diagnostic term in 1983.: 1060  Until the late 1990s, many non-epithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors". Histopathologists were unable to specifically distinguish among types we now know to be dissimilar molecularly. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types. Additionally, in the absence of specific therapy, the diagnostic categorization had only a limited influence on prognosis and therapy. The understanding of GIST biology changed significantly with identification of the molecular basis of GIST,: 1065  particularly c-KIT. Historically, literature reviews prior to the molecular definition of GIST, and for a short time thereafter, asserted that 70-80% of GISTs were benign. The identification of a molecular basis for GIST led to the exclusion of many tumors that had been considered as GIST previously, and also the incorporation of a much larger number of tumors that had been labeled as other types of sarcomas and undifferentiated carcinomas.: 1065  For example, some previous diagnoses of stomach and small bowel leiomyosarcomas (malignant tumor of smooth muscle) would be reclassified as GISTs on the basis of immunohistochemical staining. All GIST tumors are now considered to have malignant potential, and no GIST tumor can be definitively classified as "benign". Hence, all GISTs are eligible for cancer staging in the AJCC (7th edition) / UICC. Nonetheless, different GISTs have different risk assessments of their tendency to recur or to metastasize, dependent on their site of origin, size, and number of mitotic figures. Due to the change in definition, clinical pathways of care before the year 2000 are largely uninformative in the current era. Signs and symptoms GISTs may present with trouble swallowing, gastrointestinal bleeding, or metastases (mainly in the liver). Intestinal obstruction is rare, due to the tumors outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made. Pathophysiology GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally not aggressive, especially when cell division rate is slow. GIST tumors commonly metastasize to the liver (in 28% of cases) and/or to the greater omentum, lesser omentum, or mesentery (in 30% of cases). Less common areas of metastasis include the lungs, subcutaneous tissue, lymph nodes or bones.GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility. Genetics Most GISTs are sporadic. Less than 5% occur as part of hereditary familial or idiopathic multitumor syndromes. These include, in descending order of frequency, neurofibromatosis Recklinghausen (NF-1), Carneys triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), germline gain-of-function mutations in c-KIT/PDGFRA, and the Carney-Stratakis syndrome. The Carney-Stratakis syndrome is a dyad of hereditary GIST and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene pathway involving the succinate dehydrogenase (SDH) subunits SDHD, SDHC and SDHB. c-KIT mutations Approximately 85% GISTs are associated with an abnormal c-KIT pathway. c-KIT is a gene that encodes for a transmembrane receptor for a growth factor termed stem cell factor (scf). The abnormal c-KIT pathway most commonly (85%) arises from mutation of the gene itself; a smaller subset of c-KIT-associated GISTs are associated with constitutive activity of the KIT enzymatic pathway, found by immunoblotting.: 1062  The c-KIT product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells. The c-KIT molecule comprises a long extracellular domain, a transmembrane segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-KITfunction independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional mutations are likely "required" for a cell with a c-KIT mutation to develop into a GIST, but the c-KIT mutation is probably the first step of this process. Mutations in the exons 11, 9 and rarely 13 and 17 of the c-KIT gene are known to occur in GIST. The tyrosine kinase function of c-KIT is important in the medical therapy for GISTs, as described below. KIT-D816V point mutations in c-KIT exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor. KIT-p.D419del (exon 8) — A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del). PDGFRA mutations Most GIST cells with wildtype (i.e. not mutated) c-KIT instead have a mutation in another gene, PDGFR-α (platelet-derived growth factor receptor alpha), which is a related tyrosine kinase. Mutations in c-KIT and PDGFrA are mutually exclusive [4][5]. Wild-type tumors Lesser numbers of GISTs appear to be associated with neither c-KIT nor PDGFR-α abnormalities.: 1062  About 10-15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene. Diagnosis CT scanning is often undertaken (see the radiology section). The definitive diagnosis is made with a biopsy, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery. A biopsy sample will be investigated under the microscope by a pathologist physician. The pathologist examines the histopathology to identify the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be confined to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen. When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 [also known as c-KIT] —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, and vimentin). Other cells that show CD117 positivity are mast cells. If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also, sequencing of KIT and PDGFRA can be used to prove the diagnosis. Imaging The purpose of radiologic imaging is to locate the lesion, evaluate for signs of invasion and detect metastasis. Features of GIST vary depending on tumor size and organ of origin. The diameter can range from a few millimeters to more than 30 cm. Larger tumors usually cause symptoms in contrast to those found incidentally which tend to be smaller and have better prognosis. Large tumors tend to exhibit malignant behavior but small GISTs may also demonstrate clinically aggressive behavior. Plain radiographs are not very helpful in the evaluation of GISTs. If an abnormality is seen, it will be an indirect sign due to the tumor mass effect on adjacent organs. On abdominal x-ray, stomach GISTs may appear as a radiopaque mass altering the shape of the gastric air shadow. Intestinal GISTs may displace loops of bowel and larger tumors may obstruct the bowel and films will show an obstructive pattern. If cavitations are present, plain radiographs will show collections of air within the tumor. Calcification is an unusual feature of GIST but if present can be visible on plain films. Barium fluoroscopic examinations and CT are commonly used to evaluate the patient with abdominal complaints. Barium swallow images show abnormalities in 80% of GIST cases. However, some GISTs may be located entirely outside the lumen of the bowel and will not be appreciated with a barium swallow. Even in cases when the barium swallow is abnormal, an MRI or CT scan must follow since it is impossible to evaluate abdominal cavities and other abdominal organs with a barium swallow alone. In a CT scan, abnormalities may be seen in 87% of patients and it should be made with both oral and intravenous contrast. Among imaging studies, MRI has the best tissue contrast, which aids in the identification of masses within the GI tract (intramural masses). Intravenous contrast material is needed to evaluate lesion vascularity. Preferred imaging modalities in the evaluation of GISTs are CT and MRI,: 20–21  and, in selected situations, endoscopic ultrasound. CT advantages include its ability to demonstrate evidence of nearby organ invasion, ascites, and metastases. The ability of an MRI to produce images in multiple planes is helpful in determining the bowel as the organ of origin (which is difficult when the tumor is very large), facilitating diagnosis. Small GISTs Since GISTs arise from the bowel layer called muscularis propria (which is deeper to the mucosa and submucosa from a luminal perspective), small GIST imaging usually suggest a submucosal process or a mass within the bowel wall. In barium swallow studies, these GISTs most commonly present with smooth borders forming right or obtuse angles with the nearby bowel wall, as seen with any other intramural mass. The mucosal surface is usually intact except for areas of ulceration, which are generally present in 50% of GISTs. Ulcerations fill with barium causing a bulls eye or target lesion appearance. In contrast-enhanced CT, small GISTs are seen as smooth, sharply defined intramural masses with homogeneous attenuation. Large GISTs As the tumor grows it may project outside the bowel (exophytic growth) and/or inside the bowel (intraluminal growth), but they most commonly grow exophytically such that the bulk of the tumor projects into the abdominal cavity. If the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity with bleeding and cavitations that can eventually ulcerate and communicate into the lumen of the bowel. In that case, barium swallow may show an air, air-fluid levels or oral contrast media accumulation within these areas. Mucosal ulcerations may also be present. In contrast-enhanced CT images, large GISTs appear as heterogeneous masses due to areas of living tumor cells surrounding bleeding, necrosis or cysts, which is radiographically seen as a peripheral enhancement pattern with a low attenuation center. In MRI studies, the degree of necrosis and bleeding affects the signal intensity pattern. Areas of bleeding within the tumor will vary its signal intensity depending on how long ago the bleeding occurred. The solid portions of the tumor are typically low signal intensity on T1-weighted images, are high signal intensity on T2-weighted images and enhanced after administration of gadolinium. Signal-intensity voids are present if there is gas within areas of necrotic tumor. Features of malignancy Malignancy is characterized by local invasion and metastases, usually to the liver, omentum and peritoneum. However, cases of metastases to bone, pleura, lungs and retroperitoneum have been seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant lymphadenopathy (swollen lymph nodes) is uncommon (<10%) and thus imaging usually shows absence of lymph node enlargement. If metastases are not present, other radiologic features suggesting malignancy include: size (>5 cm), heterogeneous enhancement after contrast administration, and ulcerations. Also, overtly malignant behavior (in distinction to malignant potential of lesser degree) is less commonly seen in gastric tumors, with a ratio of behaviorally benign to overtly malignant of 3-5:1. Even if radiographic malignant features are present, these findings may also represent other tumors and definitive diagnosis must be made immunochemically. Management For localized, resectable adult GISTs, if anatomically and physiologically feasible, surgery is the primary treatment of choice.: 69  Surgery can be potentially curative, but watchful waiting may be considered in small tumors in carefully selected situations. Post-surgical adjuvant treatment may be recommended. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective for removal of these tumors without needing large incisions. The clinical issues of exact surgical indications for tumor size are controversial. The decision of appropriate laparoscopic surgery is affected by tumor size, location, and growth pattern.Radiotherapy has not historically been effective for GISTs: 1122  and GISTs do not respond to most chemotherapy medications,: 1122  with responses in less than 5%.: 1065  However, four medications have been identified for clinical benefit in GIST: imatinib, sunitinib, regorafenib, and ripretinib. Imatinib (Glivec/Gleevec), an orally administered drug initially marketed for chronic myelogenous leukemia based on bcr-abl inhibition, also inhibits both c-KIT tyrosine kinase mutations and PDGFRA mutations other than D842V, and is useful in treating GISTs in several situations. Imatinib has been used in selected neoadjuvant settings.: 23  In the adjuvant treatment setting, the majority of GIST tumors are cured by surgery, and do not need adjuvant therapy. An exception to this is where the anatomical position of the tumour means that surgery is technically difficult or complex. For example, rectal GIST often requires radical surgery to achieve complete resection, involving abdominoperineal resection and permanent stoma. In these situations, the use of neoadjuvant imatinib can significantly decrease both tumour size and mitotic activity, and permit less radical sphincter-preserving surgery.A substantial proportion of GIST tumors have a high risk of recurrence as estimated by a number of validated risk stratification schemes, and can be considered for adjuvant therapy. The selection criteria underpinning the decision for possible use of imatinib in these settings, including a risk assessment based on pathological factors such as tumor size, mitotic rate and location, can be used to predict the risk of recurrence in GIST patients. Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger or more aggressive tumors. Following surgical resection of GISTs, adjuvant treatment with imatinib reduces the risk of disease recurrence in higher risk groups. In selected higher risk adjuvant situations, imatinib is recommended for 3 years.Imatinib was approved for metastatic and unresectable GIST by the US FDA, February 1, 2002. The two-year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.If resistance to imatinib is encountered, the multiple tyrosine kinase inhibitor sunitinib (marketed as Sutent) can be considered.: 26 and 31 The effectiveness of imatinib and sunitinib depend on the genotype. c-KIT- and PDGFRA-mutation negative GIST tumors are usually resistant to treatment with imatinib, as is neurofibromatosis-1-associated wild-type GIST. A specific subtype of PDGFRA mutation, D842V, is also insensitive to imatinib. Recently, in PDGFRA-mutated GIST, avapritinib has been approved by FDA. Now there are real-world data coming for avapritinib as well (Dr Sameer Rastogi, et al.)Regorafenib (Stivarga) was FDA-approved in 2013 for advanced GISTs that cannot be surgically removed and that no longer respond to imatinib (Gleevec) and sunitinib (Sutent). Epidemiology GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagnosing GISTs. The estimated incidence of GIST in the United States is approximately 5000 cases annually.: 1063  This makes GIST the most common form of sarcoma, which constitutes more than 70 types of cancer. The majority of GISTs present at ages 50–70 years. Across most of the age spectrum, the incidence of GIST is similar in men and women.: 1122 Adult GISTs are rare before age 40. Pediatric GISTs are considered to be biologically distinct. Unlike GISTs at other ages, pediatric GISTs are more common in girls and young women. They appear to lack oncogenic activating tyrosine kinase mutations in both KIT and PDGFRA. Pediatric GISTs are treated differently from adult GISTs. Although the generally accepted definition of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger, "pediatric-type" GISTs can be seen in adults, which affects risk assessment, the role of lymph node resection, and choice of therapy. Citations General sources de Silva CM, Reid R (2003). "Gastrointestinal stromal tumors (GIST): c-KIT mutations, CD117 expression, differential diagnosis and targeted cancer therapy with Imatinib" (PDF). Pathol Oncol Res. 9 (1): 13–9. doi:10.1007/BF03033708. PMID 12704441. S2CID 3814815. Kitamura Y, Hirota S, Nishida T (Apr 2003). "Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors". Cancer Sci. 94 (4): 315–20. doi:10.1111/j.1349-7006.2003.tb01439.x. PMID 12824897. S2CID 31070671. External links GIST Cancer UK Surgery Questions in GIST ESUN (August 15, 2006) SPAEN (Sarcoma Patients EuroNet) - European Network of Sarcoma, GIST and Desmoid Patient Advocacy Groups GIST Support International Life Raft Group International GIST Advocacy Organization American Cancer Society Patient Guide to GIST tumors. Cancer.Net: Gastrointestinal Stromal Tumor

Accidental

Accidental may refer to: Accidental (music), a symbol which changes the pitch of a note Accidental (album), by Fred Frith Accidental (biology), a biological phenomenon more commonly known as vagrancy The Accidental, a 2005 novel by Ali Smith The Accidental (band), a UK folk band Accidental property, a philosophical term See also Accidence (or inflection), a modification of a word to express different grammatical categories Accident (disambiguation) Adventitious, which is closely related to "accidental" as used in philosophy and in biology Random, which often is used incorrectly where accidental or adventitious would be appropriate

Overweight

Being overweight or fat is having more body fat than is optimally healthy. Being overweight is especially common where food supplies are plentiful and lifestyles are sedentary. As of 2003, excess weight reached epidemic proportions globally, with more than 1 billion adults being either overweight or obese. In 2013, this increased to more than 2 billion. Increases have been observed across all age groups. A healthy body requires a minimum amount of fat for proper functioning of the hormonal, reproductive, and immune systems, as thermal insulation, as shock absorption for sensitive areas, and as energy for future use; however, the accumulation of too much storage fat can impair movement, flexibility, and alter the appearance of the body. Classification The degree to which a person is overweight is generally described by the body mass index (BMI). Overweight is defined as a BMI of 25 or more, thus it includes pre-obesity defined as a BMI between 25 and 29.9 and obesity as defined by a BMI of 30 or more. Pre-obese and overweight however are often used interchangeably, thus giving overweight a common definition of a BMI of between 25 and 29.9. There are, however, several other common ways to measure the amount of adiposity or fat present in an individuals body. Body mass indexThe body mass index (BMI) is a measure of a persons weight taking into account their height. It is given by the following formula: BMI equals a persons weight (mass) in kilograms divided by the square of the persons height in metres. The units therefore are kg/m2 but BMI measures are typically used and written without units.BMI provides a significantly more accurate representation of body fat content than simply measuring a persons weight. It is only moderately correlated with both body fat percentage and body fat mass (R2 of 0.68). It does not take into account certain factors such as pregnancy or bodybuilding; however, the BMI is an accurate reflection of fat percentage in the majority of the adult population.Body volume indexThe body volume index (BVI) was devised in 2000 as a computer, rather than manual, measurement of the human body for obesity and an alternative to the BMIBVI uses 3D software to create an accurate image of a person so BVI can differentiate between people with the same BMI rating, but who have a different shape and different weight distribution. BVI measures where a persons weight and the fat are located on the body, rather than total weight or total fat content and places emphasis on the weight carried around the abdomen, commonly known as central obesity. There has been an acceptance in recent years that abdominal fat and weight around the abdomen constitute a greater health risk.Simple weighingA persons weight is measured and compared to an estimated ideal weight. This is the easiest and most common method, but by far the least accurate, as it only measures one quantity (weight) and often does not take into account many factors such as height, body type, and relative amount of muscle mass.Skinfold calipers or "pinch test"The skin at several specific points on the body is pinched and the thickness of the resulting fold is measured. This measures the thickness of the layers of fat located under the skin, from which a general measurement of total amount of fat in the body is calculated. This method can be reasonably accurate for many people, but it assumes particular fat distribution patterns over the body—which may not apply to all individuals, and does not account for fat deposits not directly under the skin. Also, as the measurement and analysis generally involves a high degree of practice and interpretation, an accurate result requires that a professional perform it. It cannot generally be done by patients themselves.Bioelectrical impedance analysisA small electric current is passed through the body to measure its electrical resistance. As fat and muscle conduct electricity differently, this method can provide a direct measurement of the body fat percentage, in relation to muscle mass. In the past, this technique could only be performed reliably by trained professionals with specialized equipment, but it is now possible to buy home testing kits that let people do this themselves with a minimum of training. Despite the improved simplicity of this process over the years, however, a number of factors can affect the results, including hydration and body temperature, so it still needs some care when taking the test to ensure that the results are accurate.Hydrostatic weighingConsidered one of the more accurate methods of measuring body fat, this technique involves complete submersion of a person in water, with special equipment to measure the persons weight while submerged. This weight is then compared with "dry weight" as recorded outside the water to determine overall body density. As fat is less dense than muscle, careful application of this technique can provide a reasonably close estimate of fat content in the body. This technique does, however, require expensive specialized equipment and trained professionals to administer it properly.Dual-energy X-ray absorptiometry (DEXA)Originally developed to measure bone density, DEXA imaging is also used to precisely determine body fat content by using the density of various body tissues to identify which portions of the body are fat. This test is generally considered very accurate, but requires a great deal of expensive medical equipment and trained professionals to perform.The most common method for discussing this subject and the one used primarily by researchers and advisory institutions is BMI. Definitions of what is considered overweight vary by ethnicity. The current definition proposed by the US National Institutes of Health (NIH) and the World Health Organization (WHO) designates whites, Hispanics and blacks with a BMI of 25 or more as overweight. For Asians, overweight is a BMI between 23 and 29.9 and obesity for all groups is a BMI of 30 or more. BMI, however, does not account extremes of muscle mass, some rare genetic factors, the very young, and a few other individual variations. Thus it is possible for an individuals with a BMI of less than 25 to have excess body fat, while others may have a BMI that is significantly higher without falling into this category. Some of the above methods for determining body fat are more accurate than BMI but are less convenient to measure. If an individual is overweight and has excess body fat it can create or lead to health risks. Reports are surfacing, however, that being mildly overweight to slightly obese – BMI being between 24 and 31.9 – may be actually beneficial and that people with a BMI between 24 and 31.9 could actually live longer than normal weight or underweight persons. Health effects While some negative health outcomes associated with obesity are accepted within the medical community, the health implications of the overweight category are more controversial. A 2016 review estimated that the risk of death increases by seven percent among overweight people with a BMI of 25 to 27.5 and 20 percent among overweight people with a BMI of 27.5 to 30. Katherine Flegal et al., however, found that the mortality rate for individuals who are classified as overweight (BMI 25 to 29.9) may actually be lower than for those with an "ideal" weight (BMI 18.5 to 24.9), noting that many studies show that the lowest mortality rate is at a BMI close to 25. The specific conclusions appear to depend on what other factors are controlled for, and Flegal has accordingly alleged that the findings from the 2016 review are driven by bias toward preconceived opinions.Being overweight has been identified as a risk factor for cancer, and Walter Willett predicts that being overweight will overtake smoking as the primary cause of cancer in developed countries as cases of smoking-related cancer dwindle. Being overweight also increases the risk of oligospermia and azoospermia in men.Psychological well-being is also at risk in the overweight individual due to social discrimination. Being overweight has been shown not to increase mortality in older people: in a study of 70 to 75-year old Australians, mortality was lowest for "overweight" individuals (BMI 25 to 29.9), while a study of Koreans found that, among those initially aged 65 or more, an increase in BMI to above 25 was not associated with increased risk of death. Causes Being overweight is generally caused by the intake of more calories (by eating) than are expended by the body (by exercise and everyday activity). Factors that may contribute to this imbalance include: Alcoholism Eating disorders (such as binge eating) Genetic predisposition Hormonal imbalances (e.g. hypothyroidism) Insufficient or poor-quality sleep Limited physical exercise and a sedentary lifestyle Poor nutrition Metabolic disorders, which could be caused by repeated attempts to lose weight by weight cycling Overeating Psychotropic medication (e.g. olanzapine) Smoking cessation and other stimulant withdrawal StressPeople who have insulin dependent diabetes and chronically overdose insulin may gain weight, while people who already are overweight may develop insulin tolerance, and in the long run develop type II diabetes. Treatment The usual treatments for overweight individuals is diet and physical exercise. Dietitians generally recommend eating several balanced meals dispersed through the day, with a combination of progressive, primarily aerobic, physical exercise. In fact, some research found benefits from physical activity, diet and behaviour changes on BMI in children from 12 to 17 years old.Considering that most of the treatment strategies are directed to change lifestyle-related behaviours of individuals (namely in dietary and physical activity), the transtheoretical model (TTM) has been used as a framework to design weight management interventions. A systematic review assessed the effectiveness of dietary and physical activity interventions based on the TTM in producing sustainable (one year or longer) weight loss in overweight and obese adults. The included studies did not allow to produce conclusive evidence about the impact of the use of this model combined with these interventions on sustainable weight loss. Nevertheless, very low quality scientific evidence suggests that this approach may lead to improvements in physical activity and dietary habits, namely increased in both exercise duration and frequency, and fruits and vegetables consumption, along with reduced dietary fat intake. Epidemiology The World Health Organization (WHO) estimated that nearly 2 billion adults worldwide, aged 18 years and older, were overweight in 2016.According to the National Health and Nutrition Examination Survey (NHANES), an estimated 71.6% of the United States adult population aged 20 and over is considered either overweight or obese, and this percentage has increased over the last four decades. See also Body image Canadian Obesity Network Fat acceptance movement Physical attractiveness References External links Obesity Epidemic: U.S. Temporal Trends 1985–2004 at the Wayback Machine (archived December 8, 2006) Ranking of Most Overweight Countries in the World 2005 at the Wayback Machine (archived June 29, 2007) World Health Organization fact sheet on obesity and overweight

Pedophilia

Pedophilia (alternatively spelt paedophilia) is a psychiatric disorder in which an adult or older adolescent experiences a primary or exclusive sexual attraction to prepubescent children. Although girls typically begin the process of puberty at age 10 or 11, and boys at age 11 or 12, criteria for pedophilia extend the cut-off point for prepubescence to age 13. A person must be at least 16 years old, and at least five years older than the prepubescent child, for the attraction to be diagnosed as pedophilia.Pedophilia is termed pedophilic disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases (ICD-11). The DSM-5 defines it as a paraphilia involving intense and recurrent sexual urges towards and fantasies about prepubescent children that have either been acted upon or which cause the person with the attraction distress or interpersonal difficulty. The ICD-11 defines it as a "sustained, focused, and intense pattern of sexual arousal—as manifested by persistent sexual thoughts, fantasies, urges, or behaviours—involving pre-pubertal children."In popular usage, the word pedophilia is often applied to any sexual interest in children or the act of child sexual abuse, including any sexual interest in minors below the local age of consent, regardless of their level of physical or mental development. This use conflates the sexual attraction to prepubescent children with the act of child sexual abuse and fails to distinguish between attraction to prepubescent and pubescent or post-pubescent minors. Researchers recommend that these imprecise uses be avoided, because although some people who commit child sexual abuse are pedophiles, child sexual abuse offenders are not pedophiles unless they have a primary or exclusive sexual interest in prepubescent children, and some pedophiles do not molest children.Pedophilia was first formally recognized and named in the late 19th century. A significant amount of research in the area has taken place since the 1980s. Although mostly documented in men, there are also women who exhibit the disorder, and researchers assume available estimates underrepresent the true number of female pedophiles. No cure for pedophilia has been developed, but there are therapies that can reduce the incidence of a person committing child sexual abuse. The exact causes of pedophilia have not been conclusively established. Some studies of pedophilia in child sex offenders have correlated it with various neurological abnormalities and psychological pathologies. In the United States, following Kansas v. Hendricks in 1997, sex offenders who are diagnosed with certain mental disorders, particularly pedophilia, can be subject to indefinite involuntary commitment. Definitions The word pedophilia comes from the Greek παῖς, παιδός (paîs, paidós), meaning "child", and φιλία (philía), "friendly love" or "friendship". Pedophilia is used for individuals with a primary or exclusive sexual interest in prepubescent children aged 13 or younger. Infantophilia is a sub-type of pedophilia; it is used to refer to a sexual preference for children under the age of 5 (especially infants and toddlers). This is sometimes referred to as nepiophilia (from the Greek: νήπιος (népios) meaning "infant" or "child," which in turn derives from "ne-" and "epos" meaning "not speaking"), though this term is rarely used in academic sources. Hebephilia is defined as individuals with a primary or exclusive sexual interest in 11- to 14-year-old pubescents. The DSM-5 does not list hebephilia among the diagnoses. While evidence suggests that hebephilia is separate from pedophilia, the ICD-10 includes early pubertal age (an aspect of hebephilia) in its pedophilia definition, covering the physical development overlap between the two philias. In addition to hebephilia, some clinicians have proposed other categories that are somewhat or completely distinguished from pedophilia; these include pedohebephilia (a combination of pedophilia and hebephilia) and ephebophilia (though ephebophilia is not considered pathological). Signs and symptoms Development Pedophilia emerges before or during puberty, and is stable over time. It is self-discovered, not chosen. For these reasons, pedophilia has been described as a disorder of sexual preference, phenomenologically similar to a heterosexual or homosexual orientation. These observations, however, do not exclude pedophilia from being classified as a mental disorder since pedophilic acts cause harm, and mental health professionals can sometimes help pedophiles to refrain from harming children.In response to misinterpretations that the American Psychiatric Association considers pedophilia a sexual orientation because of wording in its printed DSM-5 manual, which distinguishes between paraphilia and what it calls "paraphilic disorder", subsequently forming a division of "pedophilia" and "pedophilic disorder", the association commented: "[S]exual orientation is not a term used in the diagnostic criteria for pedophilic disorder and its use in the DSM-5 text discussion is an error and should read sexual interest." They added, "In fact, APA considers pedophilic disorder a paraphilia, not a sexual orientation. This error will be corrected in the electronic version of DSM-5 and the next printing of the manual." They said they strongly support efforts to criminally prosecute those who sexually abuse and exploit children and adolescents, and "also support continued efforts to develop treatments for those with pedophilic disorder with the goal of preventing future acts of abuse." Comorbidity and personality traits Studies of pedophilia in child sex offenders often report that it co-occurs with other psychopathologies, such as low self-esteem, depression, anxiety, and personality problems. It is not clear whether these are features of the disorder itself, artifacts of sampling bias, or consequences of being identified as a sex offender. One review of the literature concluded that research on personality correlates and psychopathology in pedophiles is rarely methodologically correct, in part owing to confusion between pedophiles and child sex offenders, as well as the difficulty of obtaining a representative, community sample of pedophiles. Seto (2004) points out that pedophiles who are available from a clinical setting are likely there because of distress over their sexual preference or pressure from others. This increases the likelihood that they will show psychological problems. Similarly, pedophiles recruited from a correctional setting have been convicted of a crime, making it more likely that they will show anti-social characteristics.Impaired self-concept and interpersonal functioning were reported in a sample of child sex offenders who met the diagnostic criteria for pedophilia by Cohen et al. (2002), which the authors suggested could contribute to motivation for pedophilic acts. The pedophilic offenders in the study had elevated psychopathy and cognitive distortions compared to healthy community controls. This was interpreted as underlying their failure to inhibit their criminal behavior. Studies in 2009 and 2012 found that non-pedophilic child sex offenders exhibited psychopathy, but pedophiles did not.Wilson and Cox (1983) studied the characteristics of a group of pedophile club members. The most marked differences between pedophiles and controls were on the introversion scale, with pedophiles showing elevated shyness, sensitivity and depression. The pedophiles scored higher on neuroticism and psychoticism, but not enough to be considered pathological as a group. The authors caution that "there is a difficulty in untangling cause and effect. We cannot tell whether paedophiles gravitate towards children because, being highly introverted, they find the company of children less threatening than that of adults, or whether the social withdrawal implied by their introversion is a result of the isolation engendered by their preference i.e., awareness of the social [dis]approbation and hostility that it evokes" (p. 324). In a non-clinical survey, 46% of pedophiles reported that they had seriously considered suicide for reasons related to their sexual interest, 32% planned to carry it out, and 13% had already attempted it.A review of qualitative research studies published between 1982 and 2001 concluded that child sexual abusers use cognitive distortions to meet personal needs, justifying abuse by making excuses, redefining their actions as love and mutuality, and exploiting the power imbalance inherent in all adult–child relationships. Other cognitive distortions include the idea of "children as sexual beings", uncontrollability of sexual behavior, and "sexual entitlement-bias". Child pornography Consumption of child pornography is a more reliable indicator of pedophilia than molesting a child, although some non-pedophiles also view child pornography. Child pornography may be used for a variety of purposes, ranging from private sexual gratification or trading with other collectors, to preparing children for sexual abuse as part of the child grooming process.Pedophilic viewers of child pornography are often obsessive about collecting, organizing, categorizing, and labeling their child pornography collection according to age, gender, sex act and fantasy. According to FBI agent Ken Lanning, "collecting" pornography does not mean that they merely view pornography, but that they save it, and "it comes to define, fuel, and validate their most cherished sexual fantasies". Lanning states that the collection is the single best indicator of what the offender wants to do, but not necessarily of what has been or will be done. Researchers Taylor and Quayle reported that pedophilic collectors of child pornography are often involved in anonymous internet communities dedicated to extending their collections. Causes Although what causes pedophilia is not yet known, researchers began reporting a series of findings linking pedophilia with brain structure and function, beginning in 2002. Testing individuals from a variety of referral sources inside and outside the criminal justice system as well as controls, these studies found associations between pedophilia and lower IQs, poorer scores on memory tests, greater rates of non-right-handedness, greater rates of school grade failure over and above the IQ differences, being below average height, greater probability of having had childhood head injuries resulting in unconsciousness, and several differences in MRI-detected brain structures.Such studies suggest that there are one or more neurological characteristics present at birth that cause or increase the likelihood of being pedophilic. Some studies have found that pedophiles are less cognitively impaired than non-pedophilic child molesters. A 2011 study reported that pedophilic child molesters had deficits in response inhibition, but no deficits in memory or cognitive flexibility. Evidence of familial transmittability "suggests, but does not prove that genetic factors are responsible" for the development of pedophilia. A 2015 study indicated that pedophilic offenders have a normal IQ.Another study, using structural MRI, indicated that male pedophiles have a lower volume of white matter than a control group. Functional magnetic resonance imaging (fMRI) has indicated that child molesters diagnosed with pedophilia have reduced activation of the hypothalamus as compared with non-pedophilic persons when viewing sexually arousing pictures of adults. A 2008 functional neuroimaging study notes that central processing of sexual stimuli in heterosexual "paedophile forensic inpatients" may be altered by a disturbance in the prefrontal networks, which "may be associated with stimulus-controlled behaviours, such as sexual compulsive behaviours". The findings may also suggest "a dysfunction at the cognitive stage of sexual arousal processing".Blanchard, Cantor, and Robichaud (2006) reviewed the research that attempted to identify hormonal aspects of pedophiles. They concluded that there is some evidence that pedophilic men have less testosterone than controls, but that the research is of poor quality and that it is difficult to draw any firm conclusion from it. While not causes of pedophilia themselves, childhood abuse by adults or comorbid psychiatric illnesses—such as personality disorders and substance abuse—are risk factors for acting on pedophilic urges. Blanchard, Cantor, and Robichaud addressed comorbid psychiatric illnesses that, "The theoretical implications are not so clear. Do particular genes or noxious factors in the prenatal environment predispose a male to develop both affective disorders and pedophilia, or do the frustration, danger, and isolation engendered by unacceptable sexual desires—or their occasional furtive satisfaction—lead to anxiety and despair?" They indicated that, because they previously found mothers of pedophiles to be more likely to have undergone psychiatric treatment, the genetic possibility is more likely.A study analyzing the sexual fantasies of 200 heterosexual men by using the Wilson Sex Fantasy Questionnaire exam determined that males with a pronounced degree of paraphilic interest (including pedophilia) had a greater number of older brothers, a high 2D:4D digit ratio (which would indicate low prenatal androgen exposure), and an elevated probability of being left-handed, suggesting that disturbed hemispheric brain lateralization may play a role in deviant attractions. Diagnosis DSM and ICD-11 The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) has a significantly larger diagnostic features section for pedophilia than the previous DSM version, the DSM-IV-TR, and states, "The diagnostic criteria for pedophilic disorder are intended to apply both to individuals who freely disclose this paraphilia and to individuals who deny any sexual attraction to prepubertal children (generally age 13 years or younger), despite substantial objective evidence to the contrary." Like the DSM-IV-TR, the manual outlines specific criteria for use in the diagnosis of this disorder. These include the presence of sexually arousing fantasies, behaviors or urges that involve some kind of sexual activity with a prepubescent child (with the diagnostic criteria for the disorder extending the cut-off point for prepubescence to age 13) for six months or more, or that the subject has acted on these urges or is distressed as a result of having these feelings. The criteria also indicate that the subject should be 16 or older and that the child or children they fantasize about are at least five years younger than them, though ongoing sexual relationships between a 12- to 13-year-old and a late adolescent are advised to be excluded. A diagnosis is further specified by the sex of the children the person is attracted to, if the impulses or acts are limited to incest, and if the attraction is "exclusive" or "nonexclusive".The ICD-10 defines pedophilia as "a sexual preference for children, boys or girls or both, usually of prepubertal or early pubertal age". Like the DSM, this systems criteria require that the person be at least 16 years of age or older before being diagnosed as a pedophile. The person must also have a persistent or predominant sexual preference for prepubescent children at least five years younger than them. The ICD-11 defines pedophilic disorder as a "sustained, focused, and intense pattern of sexual arousal—as manifested by persistent sexual thoughts, fantasies, urges, or behaviours—involving pre-pubertal children." It also states that for a diagnosis of pedophilic disorder, "the individual must have acted on these thoughts, fantasies or urges or be markedly distressed by them. This diagnosis does not apply to sexual behaviours among pre- or post-pubertal children with peers who are close in age."Several terms have been used to distinguish "true pedophiles" from non-pedophilic and non-exclusive offenders, or to distinguish among types of offenders on a continuum according to strength and exclusivity of pedophilic interest, and motivation for the offense (see child sexual offender types). Exclusive pedophiles are sometimes referred to as true pedophiles. They are sexually attracted to prepubescent children, and only prepubescent children. Showing no erotic interest in adults, they can only become sexually aroused while fantasizing about or being in the presence of prepubescent children, or both. Non-exclusive offenders—or "non-exclusive pedophiles"—may at times be referred to as non-pedophilic offenders, but the two terms are not always synonymous. Non-exclusive offenders are sexually attracted to both children and adults, and can be sexually aroused by both, though a sexual preference for one over the other in this case may also exist. If the attraction is a sexual preference for prepubescent children, such offenders are considered pedophiles in the same vein as exclusive offenders.Neither the DSM nor the ICD-11 diagnostic criteria require actual sexual activity with a prepubescent youth. The diagnosis can therefore be made based on the presence of fantasies or sexual urges even if they have never been acted upon. On the other hand, a person who acts upon these urges yet experiences no distress about their fantasies or urges can also qualify for the diagnosis. Acting on sexual urges is not limited to overt sex acts for purposes of this diagnosis, and can sometimes include indecent exposure, voyeuristic or frotteuristic behaviors, or masturbating to child pornography. Often, these behaviors need to be considered in-context with an element of clinical judgment before a diagnosis is made. Likewise, when the patient is in late adolescence, the age difference is not specified in hard numbers and instead requires careful consideration of the situation.Ego-dystonic sexual orientation (66.1 F 66.1) includes people who acknowledge that they have a sexual preference for prepubertal children, but wish to change it due to the associated psychological or behavioral problems (or both). Debate regarding criteria There was discussion on the DSM-IV-TR being overinclusive and underinclusive. Its criterion A concerns sexual fantasies or sexual urges regarding prepubescent children, and its criterion B concerns acting on those urges or the urges causing marked distress or interpersonal difficulty. Several researchers discussed whether or not a "contented pedophile"—an individual who fantasizes about having sex with a child and masturbates to these fantasies, but does not commit child sexual abuse, and who does not feel subjectively distressed afterward—met the DSM-IV-TR criteria for pedophilia since this person did not meet criterion B. Criticism also concerned someone who met criterion B, but did not meet criterion A. A large-scale survey about usage of different classification systems showed that the DSM classification is only rarely used. As an explanation, it was suggested that the underinclusiveness, as well as a lack of validity, reliability and clarity might have led to the rejection of the DSM classification.Ray Blanchard, an American-Canadian sexologist known for his research studies on pedophilia, addressed (in his literature review for the DSM-5) the objections to the overinclusiveness and under underinclusiveness of the DSM-IV-TR, and proposed a general solution applicable to all paraphilias. This meant namely a distinction between paraphilia and paraphilic disorder. The latter term is proposed to identify the diagnosable mental disorder which meets Criterion A and B, whereas an individual who does not meet Criterion B can be ascertained but not diagnosed as having a paraphilia. Blanchard and a number of his colleagues also proposed that hebephilia become a diagnosable mental disorder under the DSM-5 to resolve the physical development overlap between pedophilia and hebephilia by combining the categories under pedophilic disorder, but with specifiers on which age range (or both) is the primary interest. The proposal for hebephilia was rejected by the American Psychiatric Association, but the distinction between paraphilia and paraphilic disorder was implemented.The American Psychiatric Association stated that "[i]n the case of pedophilic disorder, the notable detail is what wasnt revised in the new manual. Although proposals were discussed throughout the DSM-5 development process, diagnostic criteria ultimately remained the same as in DSM-IV TR" and that "[o]nly the disorder name will be changed from pedophilia to pedophilic disorder to maintain consistency with the chapters other listings." If hebephilia had been accepted as a DSM-5 diagnosable disorder, it would have been similar to the ICD-10 definition of pedophilia that already includes early pubescents, and would have raised the minimum age required for a person to be able to be diagnosed with pedophilia from 16 years to 18 years (with the individual needing to be at least 5 years older than the minor).ODonohue, however, suggests that the diagnostic criteria for pedophilia be simplified to the attraction to children alone if ascertained by self-report, laboratory findings, or past behavior. He states that any sexual attraction to children is pathological and that distress is irrelevant, noting "this sexual attraction has the potential to cause significant harm to others and is also not in the best interests of the individual." Also arguing for behavioral criteria in defining pedophilia, Howard E. Barbaree and Michael C. Seto disagreed with the American Psychiatric Associations approach in 1997 and instead recommended the use of actions as the sole criterion for the diagnosis of pedophilia, as a means of taxonomic simplification. Treatment General There is no evidence that pedophilia can be cured. Instead, most therapies focus on helping pedophiles refrain from acting on their desires. Some therapies do attempt to cure pedophilia, but there are no studies showing that they result in a long-term change in sexual preference. Michael Seto suggests that attempts to cure pedophilia in adulthood are unlikely to succeed because its development is influenced by prenatal factors. Pedophilia appears to be difficult to alter but pedophiles can be helped to control their behavior, and future research could develop a method of prevention.There are several common limitations to studies of treatment effectiveness. Most categorize their participants by behavior rather than erotic age preference, which makes it difficult to know the specific treatment outcome for pedophiles. Many do not select their treatment and control groups randomly. Offenders who refuse or quit treatment are at higher risk of offending, so excluding them from the treated group, while not excluding those who would have refused or quit from the control group, can bias the treated group in favor of those with lower recidivism. The effectiveness of treatment for non-offending pedophiles has not been studied. Cognitive behavioral therapy Cognitive behavioral therapy (CBT) aims to reduce attitudes, beliefs, and behaviors that may increase the likelihood of sexual offenses against children. Its content varies widely between therapists, but a typical program might involve training in self-control, social competence and empathy, and use cognitive restructuring to change views on sex with children. The most common form of this therapy is relapse prevention, where the patient is taught to identify and respond to potentially risky situations based on principles used for treating addictions.The evidence for cognitive behavioral therapy is mixed. A 2012 Cochrane Review of randomized trials found that CBT had no effect on risk of reoffending for contact sex offenders. Meta-analyses in 2002 and 2005, which included both randomized and non-randomized studies, concluded that CBT reduced recidivism. There is debate over whether non-randomized studies should be considered informative. More research is needed. Behavioral interventions Behavioral treatments target sexual arousal to children, using satiation and aversion techniques to suppress sexual arousal to children and covert sensitization (or masturbatory reconditioning) to increase sexual arousal to adults. Behavioral treatments appear to have an effect on sexual arousal patterns during phallometric testing, but it is not known whether the effect represents changes in sexual interests or changes in the ability to control genital arousal during testing, nor whether the effect persists in the long term. For sex offenders with mental disabilities, applied behavior analysis has been used. Sex drive reduction Pharmacological interventions are used to lower the sex drive in general, which can ease the management of pedophilic feelings, but does not change sexual preference. Antiandrogens work by interfering with the activity of testosterone. Cyproterone acetate (Androcur) and medroxyprogesterone acetate (Depo-Provera) are the most commonly used. The efficacy of antiandrogens has some support, but few high-quality studies exist. Cyproterone acetate has the strongest evidence for reducing sexual arousal, while findings on medroxyprogesterone acetate have been mixed.Gonadotropin-releasing hormone analogues such as leuprorelin (Lupron), which last longer and have fewer side-effects, are also used to reduce libido, as are selective serotonin reuptake inhibitors. The evidence for these alternatives is more limited and mostly based on open trials and case studies. All of these treatments, commonly referred to as "chemical castration", are often used in conjunction with cognitive behavioral therapy. According to the Association for the Treatment of Sexual Abusers, when treating child molesters, "anti-androgen treatment should be coupled with appropriate monitoring and counseling within a comprehensive treatment plan." These drugs may have side-effects, such as weight gain, breast development, liver damage and osteoporosis.Historically, surgical castration was used to lower sex drive by reducing testosterone. The emergence of pharmacological methods of adjusting testosterone has made it largely obsolete, because they are similarly effective and less invasive. It is still occasionally performed in Germany, the Czech Republic, Switzerland, and a few U.S. states. Non-randomized studies have reported that surgical castration reduces recidivism in contact sex offenders. The Association for the Treatment of Sexual Abusers opposes surgical castration and the Council of Europe works to bring the practice to an end in Eastern European countries where it is still applied through the courts. Epidemiology Pedophilia and child molestation The prevalence of pedophilia in the general population is not known, but is estimated to be lower than 5% among adult men. Less is known about the prevalence of pedophilia in women, but there are case reports of women with strong sexual fantasies and urges towards children. Male perpetrators account for the vast majority of sexual crimes committed against children. Among convicted offenders, 0.4% to 4% are female, and one literature review estimates that the ratio of male-to-female child molesters is 10 to 1. The true number of female child molesters may be underrepresented by available estimates, for reasons including a "societal tendency to dismiss the negative impact of sexual relationships between young boys and adult women, as well as womens greater access to very young children who cannot report their abuse", among other explanations.The term pedophile is commonly used by the public to describe all child sexual abuse offenders. This usage is considered problematic by researchers, because many child molesters do not have a strong sexual interest in prepubescent children, and are consequently not pedophiles. There are motives for child sexual abuse that are unrelated to pedophilia, such as stress, marital problems, the unavailability of an adult partner, general anti-social tendencies, high sex drive or alcohol use. As child sexual abuse is not automatically an indicator that its perpetrator is a pedophile, offenders can be separated into two types: pedophilic and non-pedophilic (or preferential and situational). Estimates for the rate of pedophilia in detected child molesters generally range between 25% and 50%. A 2006 study found that 35% of its sample of child molesters were pedophilic. Pedophilia appears to be less common in incest offenders, especially fathers and step-fathers. According to a U.S. study on 2429 adult male sex offenders who were categorized as "pedophiles", only 7% identified themselves as exclusive; indicating that many or most child sexual abusers may fall into the non-exclusive category.Some pedophiles do not molest children. Little is known about this population because most studies of pedophilia use criminal or clinical samples, which may not be representative of pedophiles in general. Researcher Michael Seto suggests that pedophiles who commit child sexual abuse do so because of other anti-social traits in addition to their sexual attraction. He states that pedophiles who are "reflective, sensitive to the feelings of others, averse to risk, abstain from alcohol or drug use, and endorse attitudes and beliefs supportive of norms and the laws" may be unlikely to abuse children. A 2015 study indicates that pedophiles who molested children are neurologically distinct from non-offending pedophiles. The pedophilic molesters had neurological deficits suggestive of disruptions in inhibitory regions of the brain, while non-offending pedophiles had no such deficits.According to Abel, Mittleman, and Becker (1985) and Ward et al. (1995), there are generally large distinctions between the characteristics of pedophilic and non-pedophilic molesters. They state that non-pedophilic offenders tend to offend at times of stress; have a later onset of offending; and have fewer, often familial, victims, while pedophilic offenders often start offending at an early age; often have a larger number of victims who are frequently extrafamilial; are more inwardly driven to offend; and have values or beliefs that strongly support an offense lifestyle.

Pedophilia

One study found that pedophilic molesters had a median of 1.3 victims for those with girl victims and 4.4 for those with boy victims. Child molesters, pedophilic or not, employ a variety of methods to gain sexual access to children. Some groom their victims into compliance with attention and gifts, while others use threats, alcohol or drugs, or physical force. History Pedophilia is believed to have occurred in humans throughout history, but was not formally named, defined or studied until the late 19th century. The term paedophilia erotica was coined in an 1886 article by the Viennese psychiatrist Richard von Krafft-Ebing but does not enter the authors Psychopathia Sexualis until the 10th German edition. A number of authors anticipated Krafft-Ebings diagnostic gesture. In Psychopathia Sexualis, the term appears in a section titled "Violation of Individuals Under the Age of Fourteen", which focuses on the forensic psychiatry aspect of child sexual offenders in general. Krafft-Ebing describes several typologies of offender, dividing them into psychopathological and non-psychopathological origins, and hypothesizes several apparent causal factors that may lead to the sexual abuse of children.Krafft-Ebing mentioned paedophilia erotica in a typology of "psycho-sexual perversion". He wrote that he had only encountered it four times in his career and gave brief descriptions of each case, listing three common traits: The individual is tainted [by heredity] (hereditär belastete) The subjects primary attraction is to children, rather than adults. The acts committed by the subject are typically not intercourse, but rather involve inappropriate touching or manipulating the child into performing an act on the subject.He mentions several cases of pedophilia among adult women (provided by another physician), and also considered the abuse of boys by homosexual men to be extremely rare. Further clarifying this point, he indicated that cases of adult men who have some medical or neurological disorder and abuse a male child are not true pedophilia and that, in his observation, victims of such men tended to be older and pubescent. He also lists pseudopaedophilia as a related condition wherein "individuals who have lost libido for the adult through masturbation and subsequently turn to children for the gratification of their sexual appetite" and claimed this is much more common.Austrian neurologist Sigmund Freud briefly wrote about the topic in his 1905 book Three Essays on the Theory of Sexuality in a section titled The Sexually immature and Animals as Sexual objects. He wrote that exclusive pedophilia was rare and only occasionally were prepubescent children exclusive objects. He wrote that they usually were the subject of desire when a weak person "makes use of such substitutes" or when an uncontrollable instinct which will not allow delay seeks immediate gratification and cannot find a more appropriate object.In 1908, Swiss neuroanatomist and psychiatrist Auguste Forel wrote of the phenomenon, proposing that it be referred to it as "Pederosis", the "Sexual Appetite for Children". Similar to Krafft-Ebings work, Forel made the distinction between incidental sexual abuse by persons with dementia and other organic brain conditions, and the truly preferential and sometimes exclusive sexual desire for children. However, he disagreed with Krafft-Ebing in that he felt the condition of the latter was largely ingrained and unchangeable.The term pedophilia became the generally accepted term for the condition and saw widespread adoption in the early 20th century, appearing in many popular medical dictionaries such as the 5th Edition of Stedmans in 1918. In 1952, it was included in the first edition of the Diagnostic and Statistical Manual of Mental Disorders. This edition and the subsequent DSM-II listed the disorder as one subtype of the classification "Sexual Deviation", but no diagnostic criteria were provided. The DSM-III, published in 1980, contained a full description of the disorder and provided a set of guidelines for diagnosis. The revision in 1987, the DSM-III-R, kept the description largely the same, but updated and expanded the diagnostic criteria. Law and forensic psychology Definitions Pedophilia is not a legal term, and having a sexual attraction to children is not illegal. In law enforcement circles, the term pedophile is sometimes used informally to refer to any person who commits one or more sexually-based crimes that relate to legally underage victims. These crimes may include child sexual abuse, statutory rape, offenses involving child pornography, child grooming, stalking, and indecent exposure. One unit of the United Kingdoms Child Abuse Investigation Command is known as the "Paedophile Unit" and specializes in online investigations and enforcement work. Some forensic science texts, such as Holmes (2008), use the term to refer to offenders who target child victims, even when such children are not the primary sexual interest of the offender. FBI agent Kenneth Lanning, however, makes a point of distinguishing between pedophiles and child molesters. Civil and legal commitment In the United States, following Kansas v. Hendricks, sex offenders who have certain mental disorders, including pedophilia, can be subject to indefinite civil commitment under various state laws (generically called SVP laws) and the federal Adam Walsh Child Protection and Safety Act of 2006. Similar legislation exists in Canada.In Kansas v. Hendricks, the US Supreme Court upheld as constitutional a Kansas law, the Sexually Violent Predator Act, under which Hendricks, a pedophile, was found to have a "mental abnormality" defined as a "congenital or acquired condition affecting the emotional or volitional capacity which predisposes the person to commit sexually violent offenses to the degree that such person is a menace to the health and safety of others", which allowed the State to confine Hendricks indefinitely irrespective of whether the State provided any treatment to him. In United States v. Comstock, this type of indefinite confinement was upheld for someone previously convicted on child pornography charges; this time a federal law was involved—the Adam Walsh Child Protection and Safety Act. The Walsh Act does not require a conviction on a sex offense charge, but only that the person be a federal prisoner, and one who "has engaged or attempted to engage in sexually violent conduct or child molestation and who is sexually dangerous to others", and who "would have serious difficulty in refraining from sexually violent conduct or child molestation if released".In the US, offenders with pedophilia are more likely to be recommended for civil commitment than non-pedophilic offenders. About half of committed offenders have a diagnosis of pedophilia. Psychiatrist Michael First writes that, since not all people with a paraphilia have difficulty controlling their behavior, the evaluating clinician must present additional evidence of volitional impairment instead of recommending commitment based on pedophilia alone. Society and culture General Pedophilia is one of the most stigmatized mental disorders. One study reported high levels of anger, fear and social rejection towards pedophiles who have not committed a crime. The authors suggested such attitudes could negatively impact child sexual abuse prevention by reducing pedophiles mental stability and discouraging them from seeking help. According to sociologists Melanie-Angela Neuilly and Kristen Zgoba, social concern over pedophilia intensified greatly in the 1990s, coinciding with several sensational sex crimes (but a general decline in child sexual abuse rates). They found that the word pedophile appeared only rarely in The New York Times and Le Monde before 1996, with zero mentions in 1991.Social attitudes towards child sexual abuse are extremely negative, with some surveys ranking it as morally worse than murder. Early research showed that there was a great deal of misunderstanding and unrealistic perceptions in the general public about child sexual abuse and pedophiles. However, a 2004 study concluded that the public was well-informed on some aspects of these subjects. Misuse of medical terminology The words pedophile and pedophilia are commonly used informally to describe an adults sexual interest in pubescent or post-pubescent persons under the age of consent. The terms hebephilia or ephebophilia may be more accurate in these cases.Another common usage of pedophilia is to refer to the act of sexual abuse itself, rather than the medical meaning, which is a preference for prepubescents on the part of the older individual (see above for an explanation of the distinction). There are also situations where the terms are misused to refer to relationships where the younger person is an adult of legal age, but is either considered too young in comparison to their older partner, or the older partner occupies a position of authority over them. Researchers state that the above uses of the term pedophilia are imprecise or suggest that they are best avoided. The Mayo Clinic states that pedophilia "is not a criminal or legal term". Pedophile advocacy groups From the late 1950s to early 1990s, several pedophile membership organizations advocated age of consent reform to lower or abolish age of consent laws, as well as for the acceptance of pedophilia as a sexual orientation rather than a psychological disorder, and for the legalization of child pornography. The efforts of pedophile advocacy groups did not gain mainstream acceptance, and today those few groups that have not dissolved have only minimal membership and have ceased their activities other than through a few websites. In contrast to these organizations, members of the support group Virtuous Pedophiles believe that child sexual abuse is wrong and seek to raise awareness that some pedophiles do not offend; this is generally not considered pedophile advocacy, as the Virtuous Pedophiles organization does not approve of the legalization of child pornography and does not support age of consent reform. Anti-pedophile activism Anti-pedophile activism encompasses opposition against pedophiles, against pedophile advocacy groups, and against other phenomena that are seen as related to pedophilia, such as child pornography and child sexual abuse. Much of the direct action classified as anti-pedophile involves demonstrations against sex offenders, against pedophiles advocating for the legalization of sexual activity between adults and children, and against Internet users who solicit sex from minors.High-profile media attention to pedophilia has led to incidents of moral panic, particularly following reports of pedophilia associated with Satanic ritual abuse and day care sex abuse. Instances of vigilantism have also been reported in response to public attention on convicted or suspected child sex offenders. In 2000, following a media campaign of "naming and shaming" suspected pedophiles in the UK, hundreds of residents took to the streets in protest against suspected pedophiles, eventually escalating to violent conduct requiring police intervention. See also Age disparity in sexual relationships Age of consent Child marriage Child sexuality Circles of Support and Accountability Gerontophilia List of paraphilias Pedobear Prevention Project Dunkelfeld Trafficking of children References Further reading Gladwell, Malcolm. "In Plain View." ("Jerry Sandusky and the Mind of a Pedophile") The New Yorker. September 24, 2012. Philby, Charlotte. "Female sexual abuse: The untold story of societys last taboo." The Independent. Saturday August 8, 2009. Bleyer, Jennifer. "How Can We Stop Pedophiles? Stop treating them like monsters." Slate. Monday September 24, 2012. Fong, Diana. Editor: Nancy Isenson. "If Im attracted to children, I must be a monster." Die Welt. May 29, 2013. External links Understanding MRI research on pedophilia Archived 2011-05-26 at the Wayback Machine Indictment from Operation Delego (PDF) (Archive) Virtuous Pedophiles, online support for non-offending pedophiles working to remain offence-free. HelpWantedPrevention.org, an online self-help course from Johns Hopkins University for managing attraction to children

Schizoaffective disorder

Schizoaffective disorder (SZA, SZD or SAD) is a mental disorder characterized by abnormal thought processes and an unstable mood. This diagnosis is made when the person has symptoms of both schizophrenia (usually psychosis) and a mood disorder: either bipolar disorder or depression. The main criterion for a diagnosis of schizoaffective disorder is the presence of psychotic symptoms for at least two weeks without any mood symptoms present. Schizoaffective disorder can often be misdiagnosed when the correct diagnosis may be psychotic depression, bipolar I disorder, schizophreniform disorder, or schizophrenia. It is imperative for providers to accurately diagnose patients, as treatment and prognosis differ greatly for most of these diagnoses.There are three forms of schizoaffective disorder: bipolar (or manic) type (marked by symptoms of schizophrenia and mania), depressive type (marked by symptoms of schizophrenia and depression), and mixed type (marked by symptoms of schizophrenia, depression, and mania). Common symptoms of the disorder include hallucinations, delusions, and disorganized speech and thinking. Auditory hallucinations, or "hearing voices", are most common. The onset of symptoms usually begins in adolescence or young adulthood. On a ranking scale of symptom progression of mental health issues relating to the schizophrenic spectrum, schizoaffective disorder falls between mood disorders and schizophrenia in regards to severity, with other disorders included on the ranking as well depending on symptoms. Schizoaffective disorder and other disorders on the schizophrenic spectrum are evaluated as a psychotic disorder in the DSM-V, so the line between psychotic or not psychotic begins at a mood disorder, as being considered not psychotic, and schizoaffective disorder along with other disorders of the schizophrenia spectrum, as being considered psychotic.Genetics (researched in the field of genomics); problems with neural circuits; chronic early, and chronic or short-term current environmental stress appear to be important causal factors. No single isolated organic cause has been found, but extensive evidence exists for abnormalities in the metabolism of tetrahydrobiopterin (BH4), dopamine, and glutamic acid in people with schizophrenia, psychotic mood disorders, and schizoaffective disorder. People with schizoaffective disorder are likely to have co-occurring conditions, including anxiety disorders and substance use disorders. While a diagnosis of schizoaffective disorder is rare in the general population, it is considered a common diagnosis among psychiatric disorders. Though schizoaffective disorder and schizophrenia are often thought of as mood disorders, DSM-V criteria classifies them as psychotic disorders. Diagnosis of schizoaffective disorder is based on DSM-V criteria as well as the presence of various symptoms such as mania, depression, and schizophrenia. The mainstay of current treatment is antipsychotic medication combined with mood stabilizer medication or antidepressant medication, or both. There is growing concern by some researchers that antidepressants may increase psychosis, mania, and long-term mood episode cycling in the disorder. When there is risk to self or others, usually early in treatment, hospitalization may be necessary. Psychiatric rehabilitation, psychotherapy, and vocational rehabilitation are very important for recovery of higher psychosocial function. As a group, people with schizoaffective disorder that were diagnosed using DSM-IV and ICD-10 criteria (which have since been updated) have a better outcome, but have variable individual psychosocial functional outcomes compared to people with mood disorders, from worse to the same. Outcomes for people with DSM-5 diagnosed schizoaffective disorder depend on data from prospective cohort studies, which have not been completed yet. The DSM-5 diagnosis was updated because DSM-IV criteria resulted in overuse of the diagnosis; that is, DSM-IV criteria led to many patients being misdiagnosed with the disorder. DSM-IV prevalence estimates were less than one percent of the population, in the range of 0.5–0.8 percent; newer DSM-5 prevalence estimates are not yet available. Signs and symptoms Schizoaffective disorder is defined by mood disorder-free psychosis in the context of a long-term psychotic and mood disorder. Psychosis must meet criterion A for schizophrenia which may include delusions, hallucinations, disorganized thinking and speech or behavior and negative symptoms. Both delusions and hallucinations are classic symptoms of psychosis. Delusions are false beliefs which are strongly held despite evidence to the contrary. Beliefs should not be considered delusional if they are in keeping with cultural beliefs. Delusional beliefs may or may not reflect mood symptoms (for example, someone experiencing depression may or may not experience delusions of guilt). Hallucinations are disturbances in perception involving any of the five senses, although auditory hallucinations (or "hearing voices") are the most common. Negative symptoms include alogia (lack of speech), blunted affect (reduced intensity of outward emotional expression), avolition (lack of motivation), and anhedonia (inability to experience pleasure). Negative symptoms can be more lasting and more debilitating than positive symptoms of psychosis. Mood symptoms are of mania, hypomania, mixed episode, or depression, and tend to be episodic rather than continuous. A mixed episode represents a combination of symptoms of mania and depression at the same time. Symptoms of mania include elevated or irritable mood, grandiosity (inflated self-esteem), agitation, risk-taking behavior, decreased need for sleep, poor concentration, rapid speech, and racing thoughts. Symptoms of depression include low mood, apathy, changes in appetite or weight, disturbances in sleep, changes in motor activity, fatigue, guilt or feelings of worthlessness, and suicidal thinking. DSM-5 states that if a patient only experiences psychotic symptoms during a mood episode, their diagnosis is Mood Disorder with Psychotic Features and not Schizophrenia or Schizoaffective Disorder. If the patient experiences psychotic symptoms without mood symptoms for longer than a two-week period, their diagnosis is either Schizophrenia or Schizoaffective Disorder. If mood disorder episodes are present for the majority and residual course of the illness and up until the diagnosis, the patient can be diagnosed with Schizoaffective Disorder. Causes A combination of genetic and environmental factors are believed to play a role in the development of schizoaffective disorder. Genetic studies do not support the view that schizophrenia, psychotic mood disorders and schizoaffective disorder are distinct etiological entities, but rather the evidence suggests the existence of common inherited vulnerability that increases the risks for all these syndromes. Some susceptibility pathways may be specific for schizophrenia, others for bipolar disorder, and yet other mechanisms and genes may confer risk for mixed schizophrenic and affective [or mood disorder] psychoses, but there is no support from genetics for the view that these are distinct disorders with distinct etiologies and pathogenesis. Laboratory studies of putative endophenotypes, brain imaging studies, and post mortem studies shed little additional light on the validity of the schizoaffective disorder diagnosis, as most studies combine subjects with different chronic psychoses in comparison to healthy subjects. Viewed broadly then, biological and environmental factors interact with a persons genes in ways which may increase or decrease the risk for developing schizoaffective disorder; exactly how this happens (the biological mechanism) is not yet known. Schizophrenia spectrum disorders, of which schizoaffective disorder is a part, have been increasingly linked to advanced paternal age at the time of conception, a known cause of genetic mutations. The physiology of people diagnosed with schizoaffective disorder appears to be similar, but not identical, to that of those diagnosed with schizophrenia and bipolar disorder; however, human neurophysiological function in normal brain and mental disorder syndromes is not fully understood.While there are various medications and treatment options for those with schizoaffective disorder, this disorder can affect a person for their entire lifespan. In some cases, this disorder can affect a persons ability to have a fulfilling social life and they may also have trouble forming bonds or relationships with others. Schizoaffective disorder is also more likely to occur in women and begins at a young age. Substance use disorder A clear causal connection between substance use and psychotic spectrum disorders, including schizoaffective disorder, has been difficult to prove. In the specific case of cannabis (marijuana), however, evidence supports a link between earlier onset of psychotic illness and cannabis use. The more often cannabis is used, particularly in early adolescence, the more likely a person is to develop a psychotic illness, with frequent use being correlated with double the risk of psychosis and schizoaffective disorder. A 2009 Yale review stated that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. While cannabis use is accepted as a contributory cause of schizoaffective disorder by many, it remains controversial, since not all young people who use cannabis later develop psychosis, but those who do use cannabis have an increased odds ratio of about 3. Certain drugs can imitate symptoms of schizophrenia (which is known to have similar symptoms to schizoaffective disorder). This is important to note when including that substance-induced psychosis should be ruled out when diagnosing patients so that patients are not misdiagnosed. Mechanisms Though the pathophysiology of schizoaffective disorder remains unclear, studies suggest that dopamine, norepinephrine, and serotonin may be factors in the development of the disorder.White matter and Grey Matter reductions in the right lentiform nucleus, left superior temporal gyrus, and right precuneus, and other areas in the brain are also characteristic of schizoaffective disorder. Deformities in white matter have also been found to worsen with time in individuals with schizoaffective disorder. Due to its role in emotional regulation, researchers believe that the hippocampus is also involved in the progression of schizoaffective disorder. Specifically, psychotic disorders (such as schizoaffective disorder) have been associated with lower hippocampal volumes. Moreover, deformities in the medial and thalamic regions of the brain have been implicated as contributing factors to the disorder as well. Diagnosis Psychosis as a symptom of a psychiatric disorder is first and foremost a diagnosis of exclusion. So a new-onset episode of psychosis cannot be considered to be a symptom of a psychiatric disorder until other relevant and known medical causes of psychosis are excluded, or ruled out. Many clinicians improperly perform, or entirely miss this step, introducing avoidable diagnostic error and misdiagnosis.An initial assessment includes a comprehensive history and physical examination. Although no biological laboratory tests exist which confirm schizoaffective disorder, biological tests should be performed to exclude psychosis associated with or caused by substance use, medications, toxins or poisons, surgical complications, or other medical illnesses. Since non-medical mental health practitioners are not trained to exclude medical causes of psychosis, people experiencing psychosis should be referred to an emergency department or hospital. Delirium should be ruled out, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, indicating other underlying factors which includes medical illnesses. Excluding medical illnesses associated with psychosis is performed by using blood tests to measure: Thyroid-stimulating hormone to exclude hypo- or hyperthyroidism, Basic electrolytes and serum calcium to rule out a metabolic disturbance, Full blood count including ESR to rule out a systemic infection or chronic disease, and Serology to exclude syphilis or HIV infection.Other investigations which may be performed include: EEG to exclude epilepsy, and an MRI or CT scan of the head to exclude brain lesions.Blood tests are not usually repeated for relapse in people with an established diagnosis of schizoaffective disorder, unless there is a specific medical indication. These may include serum BSL if olanzapine has previously been prescribed, thyroid function if lithium has previously been taken to rule out hypothyroidism, liver function tests if chlorpromazine has been prescribed, CPK levels to exclude neuroleptic malignant syndrome, and a urinalysis and serum toxicology screening if substance use is suspected. Assessment and treatment may be done on an outpatient basis; admission to an inpatient facility is considered if there is a risk to self or others. Because psychosis may be precipitated or exacerbated by common classes of psychiatric medications, such as antidepressants, ADHD stimulant medications, and sleep medications, prescribed medication-induced psychosis should be ruled out, particularly for first-episode psychosis. This is an essential step to reduce diagnostic error and to evaluate potential medication sources of further patient harm. Regarding prescribed medication sources of patient harm, Yale School of Medicine Professor of Psychiatry Malcolm B. Bowers, Jr, MD wrote: Illicit drugs arent the only ones that precipitate psychosis or mania—prescribed drugs can too, and in particular, some psychiatric drugs. We investigated this and found that about 1 in 12 psychotic or manic patients in an inpatient psychiatric facility are there due to antidepressant-induced psychosis or mania. Thats unfortunate for the field [of psychiatry] and disastrous for some of our patients. It is important to be understood here. I want to call attention to the fact that some persons with a family history of even the subtler forms of bipolar disorder or psychosis are more vulnerable than others to the mania- or psychosis-inducing potential of antidepressants, stimulants and sleeping medications. While Im not making a blanket statement against these medications, I am urging caution in their use. I believe [clinicians] should ask patients and their families whether there is a family history of bipolar disorder or psychosis before prescribing these medications. Most patients and their families dont know the answer when they are first asked, so time should be allowed for the patient to ask family or relatives, between the session when asked by [the clinician] and a follow-up session. This may increase the wait for a medication slightly, but because some patients are vulnerable, this is a necessary step for [the clinician] to take. I believe that psychiatry as a field has not emphasized this point sufficiently. As a result, some patients have been harmed by the very treatments that were supposed to help them; or to the disgrace of psychiatry, harmed and then misdiagnosed. Substance-induced psychosis should also be ruled out. Both substance- and medication-induced psychosis can be excluded to a high level of certainty while the person is psychotic, typically in an emergency department, using both a Broad spectrum urine toxicology screening, and a Full serum toxicology screening (of the blood).Some dietary supplements may also induce psychosis or mania, but cannot be ruled out with laboratory tests. So a psychotic persons family, partner, or friends should be asked whether he or she is currently taking any dietary supplements.Common mistakes made when diagnosing psychotic patients include: Not properly excluding delirium, Missing a toxic psychosis by not screening for substances and medications, Not appreciating medical abnormalities (e.g., vital signs), Not obtaining a medical history and family history, Indiscriminate screening without an organizing framework, Not asking family or others about dietary supplements, Premature diagnostic closure, and Not revisiting or questioning the initial diagnostic impression of primary psychiatric disorder.Schizoaffective disorder can only be diagnosed among those who have undergone a clinical evaluation with a psychiatrist. The criterion includes mental and physical symptoms such as, hallucinations or delusions, and depressive episodes. There are also links to bad hygiene and a troubled social life for those with schizoaffective disorder. Research has failed to conclusively demonstrate a positive relationship between schizoaffective disorder and substance abuse. There are several theorized causations for the onset of Schizoaffective disorder, including, genetics, general brain function, like chemistry, and structure, and stress.Only after these relevant and known causes of psychosis have been ruled out can a psychiatric differential diagnosis be made. A mental health clinician will incorporate family history, observation of a psychotic persons behavior while the person is experiencing active symptoms, to begin a psychiatric differential diagnosis. Diagnosis also includes self-reported experiences, as well as behavioral abnormalities reported by family members, friends, or significant others. Mistakes in this stage include: Not screening for dissociative disorders. Dissociative identity disorder and psychotic symptoms in schizoaffective disorder have considerable overlap, yet a different overall treatment approach. DSM-5 criteria The most widely used criteria for diagnosing schizoaffective disorder are from the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders-5.The DSM-IV schizoaffective disorder definition was plagued by problems of being inconsistently (or unreliably) used on patients; when the diagnosis is made, it does not stay with most patients over time, and it has questionable diagnostic validity (that is, it does not describe a distinct disorder, nor predict any particular outcome). These problems have been slightly reduced (or "modestly improved") in the DSM-5 according to Carpenter.When psychotic symptoms are confined to an episode of mania or depression (with or without mixed features), the diagnosis is that of a “psychotic” mood disorder, namely either psychotic bipolar disorder or psychotic major depression. Only when psychotic states persist in a sustained fashion for two weeks or longer without concurrent affective symptoms is the diagnosis schizoaffective disorder, schizophreniform disorder or schizophrenia.The second cardinal guideline in the DSM-5 diagnosis of schizoaffective disorder is one of timeframe. DSM-5 requires two episodes of psychosis (whereas DSM-IV needed only one) to qualify for the schizoaffective disorder diagnosis. As such, it is no longer an "episode diagnosis." The new schizoaffective framework looks at the time from "the [first episode of] psychosis up to the current episode [of psychosis], rather than only defining a single episode with [co-occurring] psychotic and mood syndromes." Specifically, one of the episodes of psychosis must last a minimum of two weeks without mood disorder symptoms, but the person may be mildly to moderately depressed while psychotic. The other period of psychosis "requires the overlap of mood [disorder] symptoms with psychotic symptoms to be conspicuous" and last for a greater portion of the disorder.These two changes are intended by the DSM-5 workgroup to accomplish two goals: Increase the diagnosis consistency (or reliability) when it is used; Significantly decrease the overall use of the schizoaffective disorder diagnosis.If the schizoaffective diagnosis is used less often, other diagnoses (like psychotic mood disorders and schizophrenia) are likely to be used more often; but this is hypothetical until real-world data arrive. Validity problems with the diagnosis remain and await further work in the fields of psychiatric genetics, neuroimaging, and cognitive science that includes the overlapping fields of cognitive, affective, and social neuroscience, which may change the way schizoaffective disorder is conceptualized and defined in future versions of the DSM and ICD. Comorbidities Schizoaffective disorder shares a high level of comorbidity with other psychiatric disorders, specifically anxiety disorders, depression, and bipolar disorder. Individuals with schizoaffective disorder are also often diagnosed with substance abuse disorder, usually relating to tobacco, marijuana, or alcohol. Health care providers indicate the importance of assessing for co-occurring substance use disorders, as multiple diagnoses not only potentially increase negative symptomology, but may also adversely affect the treatment of schizoaffective disorder. Types One of three types of schizoaffective disorder may be noted in a diagnosis based on the mood component of the disorder: Bipolar type, when the disturbance includes manic episodes, hypomania, or mixed episodes—major depressive episodes also typically occur; Depressive type, when the disturbance includes major depressive episodes exclusively—that is, without manic, hypomanic, or mixed episodes. Mixed type, when the disturbance includes both manic and depressive symptoms, but psychotic symptoms exist separately from bipolar disorder. Problems with DSM-IV schizoaffective disorder The American Psychiatric Associations DSM-IV criteria for schizoaffective disorder persisted for 19 years (1994–2013). Clinicians adequately trained in diagnosis used the schizoaffective diagnosis too often, largely because the criteria were poorly defined, ambiguous, and hard to use (or poorly operationalized). Poorly trained clinicians used the diagnosis without making necessary exclusions of common causes of psychosis, including some prescribed psychiatric medications. Specialty books written by experts on schizoaffective disorder have existed for over eight years before DSM-5 describing the overuse of the diagnosis.Carpenter and the DSM-5 schizoaffective disorders workgroup analyzed data made available to them in 2009, and reported in May 2013 that: a recent review of psychotic disorders from large private insurance and Medicare databases in the U.S. found that the diagnosis of DSM-IV schizoaffective disorder was used for about a third of cases with non-affective psychotic disorders. Hence, this unreliable and poorly defined diagnosis is clearly overused. As stated above, the DSM-IV schizoaffective disorder diagnosis is very inconsistently used or unreliable. A diagnosis is unreliable when several different mental health professionals observing the same individual make different diagnoses excessively. Even when a structured DSM-IV diagnostic interview and best estimate procedures were made by experts in the field that included information from family informants and prior clinical records, reliability was still poor for the DSM-IV schizoaffective diagnosis.The DSM-IV schizoaffective diagnosis is not stable over time either. An initial diagnosis of schizoaffective disorder during time spent at a psychiatric inpatient facility was stable at 6-month and 24-month follow ups for only 36% of patients. By comparison, diagnostic stability was 92% for schizophrenia, 83% for bipolar disorder and 74% for major depression. Most patients diagnosed with DSM-IV schizoaffective disorder are later diagnosed with a different disorder, and that disorder is more stable over time than the DSM-IV schizoaffective disorder diagnosis.In April 2009, Carpenter and the DSM-5 schizoaffective disorder workgroup reported that they were "developing new criteria for schizoaffective disorder to improve reliability and face validity," and were "determining whether the dimensional assessment of mood [would] justify a recommendation to drop schizoaffective disorder as a diagnostic category." Speaking to an audience at the May 2009 annual conference of the American Psychiatric Association, Carpenter said: We had hoped to get rid of schizoaffective [disorder] as a diagnostic category [in the DSM-5] because we dont think its [a] valid [scientific entity] and we dont think its reliable. On the other hand, we think its absolutely indispensable to clinical practice. A major reason why DSM-IV schizoaffective disorder was indispensable to clinical practice is because it offered clinicians a diagnosis for patients with psychosis in the context of mood disorder whose clinical picture, at the time diagnosed, appeared different from DSM-IV "schizophrenia" or "mood disorder with psychotic features". But DSM-IV schizoaffective disorder carries an unnecessarily worse prognosis than a "mood disorder with psychotic features" diagnosis, because long-term data revealed that a significant proportion of DSM-IV schizoaffective disorder patients had 15-year outcomes indistinguishable from patients with mood disorders with or without psychotic features, even though the clinical picture at the time of first diagnosis looked different from both schizophrenia and mood disorders.These problems with the DSM-IV schizoaffective disorder definition result in most people the diagnosis is used on being misdiagnosed; furthermore, outcome studies done 10 years after the diagnosis was released showed that the group of patients defined by the DSM-IV and ICD-10 schizoaffective diagnosis had significantly better outcomes than predicted, so the diagnosis carries a misleading and unnecessarily poor prognosis. The DSM-IV criteria for schizoaffective disorder will continue to be used on U.S. board examinations in psychiatry through the end of 2014; established practitioners may continue to use the problematic DSM-IV definition much further into the future also. DSM-5 research directions The new schizoaffective disorder criteria continue to have questionable diagnostic validity. Questionable diagnostic validity does not doubt that people with symptoms of psychosis and mood disorder need treatment—psychosis and mood disorder must be treated. Instead, questionable diagnostic validity means there are unresolved problems with the way the DSM-5 categorizes and defines schizoaffective disorder. A core concept in modern psychiatry since DSM-III was released in 1980, is the categorical separation of mood disorders from schizophrenia, known as the Kraepelinian dichotomy. Emil Kraepelin introduced the idea that schizophrenia was separate from mood disorders after observing patients with symptoms of psychosis and mood disorder, over a century ago, in 1898. This was a time before genetics were known and before any treatments existed for mental illness. The Kraepelinian dichotomy was not used for DSM-I and DSM-II because both manuals were influenced by the dominant psychodynamic psychiatry of the time, but the designers of DSM-III wanted to use more scientific and biological definitions. Consequently, they looked to psychiatrys history and decided to use the Kraepelinian dichotomy as a foundation for the classification system. The Kraepelinian dichotomy continues to be used in DSM-5 despite having been challenged by data from modern psychiatric genetics for over eight years, and there is now evidence of a significant overlap in the genetics of schizophrenia and bipolar disorder. According to this genetic evidence, the Kraepelinian categorical separation of mood disorders from schizophrenia at the foundation of the current classification and diagnostic system is a mistaken false dichotomy.The dichotomy at the foundation of the current system forms the basis for a convoluted schizoaffective disorder definition in DSM-IV that resulted in excessive misdiagnosis. Real life schizoaffective disorder patients have significant and enduring symptoms that bridge what are incorrectly assumed to be categorically separate disorders, schizophrenia and bipolar disorder. People with psychotic depression, bipolar disorder with a history of psychosis, and schizophrenia with mood symptoms also have symptoms that bridge psychosis and mood disorders. The categorical diagnostic manuals do not reflect reality in their separation of psychosis (via the schizophrenia diagnosis) from mood disorder, nor do they currently emphasize the actual overlap found in real-life patients. Thus, they are likely to continue to introduce either-or conceptual and diagnostic error, by way of confirmation bias into clinicians mindsets, hindering accurate assessment and treatment.The new definition continues the lack of parsimony of the old definition. Simpler, clearer, and more usable definitions of the diagnosis were supported by certain members of the DSM-5 workgroup (see next paragraph); these were debated but deemed premature, because more "research [is] needed to establish a new classification system of equal or greater validity" to the existing system. Because of DSM-5s continuing problematic categorical foundation, schizoaffective disorders conceptual and diagnostic validity remains doubtful. After enough research is completed and data exists, future diagnostic advances will need to either eliminate and replace, or soften and bridge, the hard categorical separation of mood disorders from schizophrenia; most likely using a spectrum or dimensional approach to diagnosis.More parsimonious definitions than the current one were considered by Carpenter and the DSM-5 workgroup: One option for the DSM-5 would have been to remove the schizoaffective disorder category and to add affective [or mood] symptoms [that is, mania, hypomania, mixed episode, or depression] as a dimension to schizophrenia and schizophreniform disorder or to define a single category for the co-occurrence of psychosis and mood symptoms. This option was extensively debated but ultimately deemed to be premature in the absence of sufficient clinical and theoretical validating data justifying such a … reconceptualization. Additionally, there appeared to be no practical way to introduce affect [or mood] dimensions covering the entire course of illness, that would capture the current concept of periods of psychosis related and unrelated to mood episodes. [N]o valid biomarkers or laboratory measures have emerged to distinguish between affective psychosis [or psychotic mood disorders] and schizophrenia. To the contrary, the idea of a dichotomy between these types of conditions has proven naïve. [T]he admixture of "schizophrenic" and affective [or mood] symptoms is a feature of many, or even most, cases with severe mental illness. Most presenting symptoms of psychosis have little validity in determining diagnosis, prognosis, or treatment response in psychosis. [U]ltimately a more … dimensional approach [to assessment and treatment] will be required. The field of psychiatry has begun to question its assumptions and analyze its data in order to merge closer with evidence-based medicine. The removal of the "episode diagnosis", and the addition of two episodes of psychosis, as qualifications for the DSM-5 schizoaffective diagnosis, may improve the diagnosis consistency over DSM-IV for research purposes, where diagnostic criteria are by necessity followed exactingly. But the new definition remains long, unwieldy, and perhaps still not very useful for community clinicians—with two psychoses, one for two weeks minimum and without mood disorder (but the person can be mildly or moderately depressed) and the other with significant mood disorder and psychosis lasting for most of the time, and with lasting mood symptoms for most of the

Schizoaffective disorder

residual portion of the illness. Community clinicians used the previous definition "for about a third of cases with non-affective psychotic disorders." Non-affective psychotic disorders are, by definition, not schizoaffective disorder. For clinicians to make such sizeable errors of misdiagnosis may imply systemic problems with the schizoaffective disorder diagnosis itself. Already, at least one expert believes the new schizoaffective definition has not gone far enough to solve the previous definitions problems.From a scientific standpoint, modern clinical psychiatry is still a very young, underdeveloped medical specialty because its target organ, the human brain, is not yet well understood. The human brains neural circuits, for example, are just beginning to be mapped by modern neuroscience in the Human Connectome Project and CLARITY. Clinical psychiatry, furthermore, has begun to understand and acknowledge its current limitations—but further steps by the field are required to significantly reduce misdiagnosis and patient harm; this is crucial both for responsible patient care and to retain public trust. Looking forward, a paradigm shift is needed in psychiatric research to address unanswered questions about schizoaffective disorder. The dimensional Research Domain Criteria project currently being developed by the U.S. National Institutes of Mental Health, may be the specific problem solving framework psychiatry needs to develop a more scientifically mature understanding of schizoaffective disorder as well as all other mental disorders. Treatment The primary treatment of schizoaffective disorder is medication, with improved outcomes using combined long-term psychological and social supports. Hospitalization may occur for severe episodes either voluntarily or (if mental health legislation allows it) involuntarily. Long-term hospitalization is uncommon since deinstitutionalization started in the 1950s, although it still occurs. Community support services including drop-in centers, visits by members of a community mental health team, supported employment and support groups are common. Evidence indicates that regular exercise has a positive effect on the physical and mental health of those with schizoaffective disorder.Because of the heterogeneous symptomology associated with schizoaffective disorder, it is common for patients to be misdiagnosed. Many people are either diagnosed with depression, schizophrenia, or bipolar disorder instead of schizoaffective disorder. Because of the broad range of symptoms of Schizoaffective disorder, patients are often misdiagnosed in a clinical setting. In fact, almost 39% of people are misdiagnosed when it comes to psychiatric disorders.While various medications and treatment options exist for those diagnosed with schizoaffective disorder, symptoms may continue to impact a person for their entire lifespan.Schizoaffective disorder can affect a persons ability to experience a fulfilling social life and they may also exhibit difficulty forming bonds or relationships with others. Schizoaffective disorder is more likely to occur in women and symptoms begin manifesting at a young age. Therapy Psychosocial treatments have been found to improve outcomes related to schizoaffective disorder. Supportive psychotherapy and cognitive behavioral therapy are both helpful. Intensive case management (ICM) has been shown to reduce hospitalizations, improve adherence to treatment, and improve social functioning. With ICM, clients are assigned a case manager responsible for coordination of care and assisting clients to access supports to address needs in multiple areas related to well-being, including housing. Psychiatric/psychosocial rehabilitation is often a component of schizoaffective disorder treatment. This rehabilitation method focuses on solving community integration problems such as obtaining and keeping housing and increasing involvement in positive social groups. It also focuses on improving and increasing activities of daily living; increasing daily healthy habits and decreasing unhealthy behaviors, thereby significantly improving quality of life. Psychiatric rehabilitation may also focus on vocational rehabilitation. Evidence suggests that cognition-based approaches may be able to improve work and social functioning.Psychiatric rehabilitation consists of eight main areas: Psychiatric (symptom reduction and management) Health and Medical (maintaining consistency of care) Housing (safe environments) Basic living skills (hygiene, meals [including increasing healthy food intake and reducing processed food intake], safety, planning and chores) Social (relationships, family boundaries, communication and integration of client into the community) Education and vocation (coping skills, motivation and suitable goals chosen by client) Finance (personal budget) Community and legal (resources) Medication Antipsychotic medication is usually required both for acute treatment and the prevention of relapse. There is no single antipsychotic of choice in treating schizoaffective disorder, but atypical antipsychotics may be considered due to their mood-stabilizing abilities. To date, paliperidone (Invega) is the only antipsychotic with FDA approval for the treatment of schizoaffective disorder. Other antipsychotics may be prescribed to further alleviate psychotic symptoms.Though not approved for treatment use by the FDA, research suggests that Clozapine may also be effective in treating schizoaffective disorder, particularly in those resistant to initial medication. Clozapine is an atypical antipsychotic that is recognized as being particularly effective when other antipsychotic agents have failed. When combined with cognitive therapy, Clozapine has been found to decrease positive and negative symptoms of psychosis at a higher rate in schizoaffective individuals. Clozapine has also been associated with a decreased risk of suicide in patients with schizoaffective disorder and a history of suicidality. Despite this, clozapine treatment may be ineffective for some patients, particularly in those that are already drug-resistant.The management of the bipolar type of schizoaffective disorder is similar to the treatment of bipolar disorder, with the goal of preventing mood episodes and cycling. Lithium or anticonvulsant mood stabilizers such as valproic acid, carbamazepine, and lamotrigine are prescribed in combination with an antipsychotic.Antidepressants have also been used to treat schizoaffective disorder. Though they may be useful in treating the depressive subtype of the disorder, research suggests that antidepressants are far less effective in treatment than antipsychotics and mood stabilizers.Some research has supported the efficacy of anxiolytics in treating schizoaffective disorder, though general findings on their effectiveness in treating schizoaffective disorder remain inconclusive. Due to the severe negative outcomes associated with many anti-anxiety drugs, many researchers have cautioned against their long term use in treatment. Electroconvulsive therapy Electroconvulsive therapy (ECT) may be considered for patients with schizoaffective disorder experiencing severe depression or severe psychotic symptoms that have not responded to treatment with antipsychotics. Epidemiology Compared to depression, schizophrenia, and bipolar disorder, schizoaffective disorder is less commonly diagnosed. Schizoaffective disorder is estimated to occur in 0.3 to 0.8 percent of people at some point in their life. 30% of cases occur between the ages of 25 and 35. It is more common in women than men; however, this is because of the high concentration of women in the depressive subcategory, whereas the bipolar subtype has a roughly even gender distribution. Children are less likely to be diagnosed with this disorder, as the onset presents itself in adolescence or young adulthood. History The term schizoaffective psychosis was introduced by the American psychiatrist Jacob Kasanin in 1933 to describe an episodic psychotic illness with predominant affective symptoms, that was thought at the time to be a good-prognosis schizophrenia. Kasanins concept of the illness was influenced by the psychoanalytic teachings of Adolf Meyer and Kasanin postulated that schizoaffective psychosis was caused by "emotional conflicts" of a "mainly sexual nature" and that psychoanalysis "would help prevent the recurrence of such attacks." He based his description on a case study of nine individuals. Other psychiatrists, before and after Kasanin, have made scientific observations of schizoaffective disorder based on assumptions of a biological and genetic cause of the illness. In 1863, German psychiatrist Karl Kahlbaum (1828–1899) described schizoaffective disorders as a separate group in his vesania typica circularis. Kahlbaum distinguished between cross-sectional and longitudinal observations. In 1920, psychiatrist Emil Kraepelin (1856–1926) observed a "great number" of cases that had characteristics of both groups of psychoses that he originally posited were two distinct and separate illnesses, dementia praecox (now called schizophrenia) and manic depressive insanity (now called bipolar disorders and recurrent depression).Kraepelin acknowledged that "there are many overlaps in this area," that is, the area between schizophrenia and mood disorders. In 1959, psychiatrist Kurt Schneider (1887–1967) began to further refine conceptualizations of the different forms that schizoaffective disorders can take since he observed "concurrent and sequential types". (The concurrent type of illness he referred to is a longitudinal course of illness with episodes of mood disorder and psychosis occurring predominantly at the same time [now called psychotic mood disorders or affective psychosis]; while his sequential type refers to a longitudinal course predominantly marked by alternating mood and psychotic episodes.) Schneider described schizoaffective disorders as "cases in-between" the traditional Kraepelinian dichotomy of schizophrenia and mood disorders.The historical clinical observation that schizoaffective disorder is an overlap of schizophrenia and mood disorders is explained by genes for both illnesses being present in individuals with schizoaffective disorder; specifically, recent research shows that schizophrenia and mood disorders share common genes and polygenic variations. Schizoaffective disorder was included as a subtype of schizophrenia in DSM-I and DSM-II, though research showed a schizophrenic cluster of symptoms in individuals with a family history of mood disorders whose illness course, other symptoms and treatment outcome were otherwise more akin to bipolar disorder than to schizophrenia. DSM-III placed schizoaffective disorder in "Psychotic Disorders Not Otherwise Specified" before being formally recognized in DSM-III-R. DSM-III-R included its own diagnostic criteria as well as the subtypes, bipolar and depressive. In DSM-IV, published in 1994, schizoaffective disorders belonged to the category "Other Psychotic Disorders" and included almost the same criteria and the same subtypes of illness as DSM-III-R, with the addition of mixed bipolar symptomatology.DSM-IV and DSM-IV-TR (published in 2000) criteria for schizoaffective disorder were poorly defined and poorly operationalized. These ambiguous and unreliable criteria lasted 19 years and led clinicians to significantly overuse the schizoaffective disorder diagnosis. Patients commonly diagnosed with DSM-IV schizoaffective disorder showed a clinical picture at time of diagnosis that appeared different from schizophrenia or psychotic mood disorders using DSM-IV criteria, but who as a group, were longitudinally determined to have outcomes indistinguishable from those with mood disorders with or without psychotic features. A poor prognosis was assumed to apply to these patients by most clinicians, and this poor prognosis was harmful to many patients. The poor prognosis for DSM-IV schizoaffective disorder was not based on patient outcomes research, but was caused by poorly defined criteria interacting with clinical tradition and belief; clinician enculturation with unscientific assumptions from the diagnosis history (discussed above), including the invalid Kraepelinian dichotomy; and by clinicians being unfamiliar with the scientific limitations of the diagnostic and classification system.The DSM-5 schizoaffective disorder workgroup analyzed all of the available research evidence on schizoaffective disorder, and concluded that "presenting symptoms of psychosis have little validity in determining diagnosis, prognosis, or treatment response." Given our understanding of overlapping genetics in bipolar disorders, schizoaffective disorder, and schizophrenia, as well as the overlap in treatments for these disorders; but given the lack of specificity of presenting symptoms for determining diagnosis, prognosis or treatment response in these psychotic illness syndromes, the limits of our knowledge are clearer: Presenting symptoms of psychosis describe only presenting symptoms to be treated, and not much more. Schizoaffective disorder was changed to a longitudinal or life course diagnosis in DSM-5 for this reason. Research Little is known of the causes and mechanisms that lead to the development of schizoaffective disorder. Whether schizoaffective disorder is a variant of schizophrenia (as in DSM-5 and ICD-10 classification systems), a variant of bipolar disorder, or part of a dimensional continuum between psychotic depression, bipolar disorders and schizophrenia is currently being investigated.More recently, some research suggests the need for a more specialized classification for schizoaffective disorder. In a 2017 examining diagnostic heterogeneity study, researchers found that when compared to a schizophrenia sample, individuals with schizoaffective disorder rate higher in suicidality and anxiety disorder comorbidity. References Further reading == External links ==

Macrocheilia

Macrocheilia is a condition of permanent swelling of the lip that results from greatly distended lymphatic spaces. This causes an abnormal largeness of the lips. This is sometimes seen in leprosy patients. See also Nevus psiloliparus List of cutaneous conditions References External links eMedicine: Lip reduction

Spinal stenosis

Spinal stenosis is an abnormal narrowing of the spinal canal or neural foramen that results in pressure on the spinal cord or nerve roots. Symptoms may include pain, numbness, or weakness in the arms or legs. Symptoms are typically gradual in onset and improve with leaning forward. Severe symptoms may include loss of bladder control, loss of bowel control, or sexual dysfunction.Causes may include osteoarthritis, rheumatoid arthritis, spinal tumors, trauma, Pagets disease of the bone, scoliosis, spondylolisthesis, and the genetic condition achondroplasia. It can be classified by the part of the spine affected into cervical, thoracic, and lumbar stenosis. Lumbar stenosis is the most common, followed by cervical stenosis. Diagnosis is generally based on symptoms and medical imaging.Treatment may involve medications, bracing, or surgery. Medications may include NSAIDs, acetaminophen, or steroid injections. Stretching and strengthening exercises may also be useful. Limiting certain activities may be recommended. Surgery is typically only done if other treatments are not effective, with the usual procedure being a decompressive laminectomy.Spinal stenosis occurs in as many as 8% of people. It occurs most commonly in people over the age of 50. Males and females are affected equally often. The first modern description of the condition is from 1803 by Antoine Portal, and there is evidence of the condition dating back to Ancient Egypt. Types The most common forms are lumbar spinal stenosis, at the level of the lower back, and cervical spinal stenosis, which are at the level of the neck. Thoracic spinal stenosis, at the level of the mid-back, is much less common.In lumbar stenosis, the spinal nerve roots in the lower back are compressed which can lead to symptoms of sciatica (tingling, weakness, or numbness that radiates from the low back and into the buttocks and legs).Cervical spinal stenosis can be far more dangerous by compressing the spinal cord. Cervical canal stenosis may lead to myelopathy, a serious condition causing symptoms including major body weakness and paralysis. Such severe spinal stenosis symptoms are virtually absent in lumbar stenosis, however, as the spinal cord terminates at the top end of the adult lumbar spine, with only nerve roots (cauda equina) continuing further down. Cervical spinal stenosis is a condition involving narrowing of the spinal canal at the level of the neck. It is frequently due to chronic degeneration, but may also be congenital or traumatic. Treatment frequently is surgical. Signs and symptoms Common Standing discomfort (94%) Discomfort/pain, in shoulder, arm, hand (78%) Bilateral symptoms (68%) Numbness at or below the level of involvement (63%) Weakness at or below the level of involvement (43%) Pain or weakness in buttock / thigh only (8%) Pain or weakness below the knee (3%) Neurological disorders Cervical (spondylotic) myelopathy, a syndrome caused by compression of the cervical spinal cord which is associated with "numb and clumsy hands", imbalance, loss of bladder and bowel control, and weakness that can progress to paralysis. Pinched nerve, causing numbness. Intermittent neurogenic claudication characterized by lower limb numbness, weakness, diffuse or radicular leg pain associated with paresthesia (bilaterally), weakness and/or heaviness in buttocks radiating into lower extremities with walking or prolonged standing. Symptoms occur with extension of spine and are relieved with spine flexion. Minimal to zero symptoms when seated or supine. Radiculopathy (with or without radicular pain) neurologic condition—nerve root dysfunction causes objective signs such as weakness, loss of sensation and of reflex. Cauda equina syndrome - Lower extremity pain, weakness, numbness that may involve perineum and buttocks, associated with bladder and bowel dysfunction. Lower back pain due to degenerative disc or joint changes. Causes Aging Any of the factors below may cause the spaces in the spine to narrow. Spinal ligaments can thicken (ligamenta flava) Bone spurs develop on the bone and into the spinal canal or foraminal openings Intervertebral discs may bulge or herniate into the canal or foraminal openings Degenerative disc disease causes narrowing of the spaces. Facet joints break down Facet joints may hypertrophy Compression fractures of the spine, which are common in osteoporosis Synovial cysts form on the facet joints causing compression of the spinal sac of nerves (thecal sac) Arthritis Osteoarthritis Rheumatoid arthritis—much less common cause of spinal problems Congenital Spinal canal is too small at birth Structural deformities of the vertebrae may cause narrowing of the spinal canal. Instability of the spine A vertebra slips forward on another (spondylolisthesis) Trauma Accidents and injuries may dislocate the spine and the spinal canal or cause burst fractures that yield fragments of bone that go through the canal. Patients with cervical myelopathy caused by narrowing of the spinal canal are at higher risks of acute spinal cord injury if involved in accidents. Tumors Irregular growths of soft tissue will cause inflammation. Growth of tissue into the canal pressing on nerves, the sac of nerves, or the spinal cord. Diagnosis The diagnosis of spinal stenosis involves a complete evaluation of the spine. The process usually begins with a medical history and physical examination. X-ray and MRI scans are typically used to determine the extent and location of the nerve compression. Medical history The medical history is the most important aspect of the examination as it will tell the physician about subjective symptoms, possible causes for spinal stenosis, and other possible causes of back pain. Physical examination The physical examination of a patient with spinal stenosis will give the physician information about exactly where nerve compression is occurring. Some important factors that should be investigated are any areas of sensory abnormalities, numbness, irregular reflexes, and any muscular weakness. MRI MRI has become the most frequently used study to diagnose spinal stenosis. The MRI uses electromagnetic signals to produce images of the spine. MRIs are helpful because they show more structures, including nerves, muscles, and ligaments, than seen on X-rays or CT scans. MRIs are helpful at showing exactly what is causing spinal nerve compression. Myelography In CT myelography, spinal tap is performed in the low back with dye injected into the spinal fluid. X-rays are performed followed by a CT scan of the spine to help see narrowing of the spinal canal. This is a very effective study in cases of lateral recess stenosis. It is also necessary for patients in which MRI is contraindicated, such as those with implanted pacemakers. Red flags Fever Nocturnal pain Gait disturbance Structural deformity Unexplained weight loss Previous carcinoma Severe pain upon lying down Recent trauma with suspicious fracture Presence of severe or progressive neurologic deficit Treatments Treatment options are either surgical or non-surgical. Overall evidence is inconclusive whether non-surgical or surgical treatment is the better for lumbar spinal stenosis. Non-surgical treatments The effectiveness of non-surgical treatments is unclear as they have not been well studied. Education about the course of the condition and how to relieve symptoms Medicines to relieve pain and inflammation, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) Exercise, to maintain or achieve overall good health, aerobic exercise, such as riding a stationary bicycle, which allows for a forward lean, walking, or swimming can relieve symptoms Weight loss, to relieve symptoms and slow progression of the stenosis Physical therapy to support self-care. Also may give instructs on stretching and strength exercises that may lead to a decrease in pain and other symptoms. Lumbar epidural steroid or anesthetic injections have low quality evidence to support their use. Surgery Lumbar decompressive laminectomy: This involves removing the roof of bone overlying the spinal canal and thickened ligaments in order to decompress the nerves and sac of nerves. 70-90% of people have good results. Interlaminar implant: This is a non-fusion U-shaped device that is placed between two bones in the lower back that maintains motion in the spine and keeps the spine stable after a lumbar decompressive surgery. The U-shaped device maintains height between the bones in the spine so nerves can exit freely and extend to lower extremities. Surgery for cervical myelopathy is either conducted from the front or from the back, depending on several factors such as where the compression occurs and how the cervical spine is aligned. Anterior cervical discectomy and fusion: A surgical treatment of nerve root or spinal cord compression by decompressing the spinal cord and nerve roots of the cervical spine with a discectomy in order to stabilize the corresponding vertebrae. Posterior approaches seek to generate space around the spinal cord by removing parts of the posterior elements of the spine. Techniques include laminectomy, laminectomy and fusion, and laminoplasty.Decompression plus fusion appears no better than decompression alone, while spinal spacers appears better than decompression plus fusion but not better than decompression alone. No differences were found in the type of decompression. Epidemiology The NAMCS data shows the incidence in the U.S. population to be 3.9% of 29,964,894 visits for mechanical back problems. The Longitudinal Framingham Heart Study found 1% of men and 1.5% of women had vertebral slippage at a mean age of 54. Over the next 25 years, 11% of men and 25% of women developed degenerative vertebral slippage. Research A RCT is being conducted in Sweden, to compare surgery versus non-surgical treatment for lumbar spinal stenosis. See also Spinal cord compression References External links "Spinal Stenosis". PubMed Health. National Center for Biotechnology Information, U.S. National Library of Medicine. 25 May 2010. Archived from the original on 8 February 2011. "Questions and Answers about Spinal Stenosis". US National Institute of Arthritis and Musculoskeletal and Skin Diseases. 11 April 2017.

Liver disease

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the signs and symptoms of a liver disease are the following: Jaundice Confusion and altered consciousness caused by hepatic encephalopathy. Thrombocytopenia and coagulopathy. Risk of bleeding symptoms particularly taking place in gastrointestinal tract Liver diseases There are more than a hundred different liver diseases. Some of the most common are: Fascioliasis, a parasitic infection of liver caused by a liver fluke of the genus Fasciola, mostly Fasciola hepatica. Hepatitis, inflammation of the liver, is caused by various viruses (viral hepatitis) also by some liver toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune hepatitis) or hereditary conditions. Alcoholic liver disease is a hepatic manifestation of alcohol overconsumption, including fatty liver disease, alcoholic hepatitis, and cirrhosis. Analogous terms such as "drug-induced" or "toxic" liver disease are also used to refer to disorders caused by various drugs. Fatty liver disease (hepatic steatosis) is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells. Non-alcoholic fatty liver disease is a spectrum of disease associated with obesity and metabolic syndrome. Hereditary diseases that cause damage to the liver include hemochromatosis, involving accumulation of iron in the body, and Wilsons disease. Liver damage is also a clinical feature of alpha 1-antitrypsin deficiency and glycogen storage disease type II. In transthyretin-related hereditary amyloidosis, the liver produces a mutated transthyretin protein which has severe neurodegenerative or cardiopathic effects. Liver transplantation can be curative. Gilberts syndrome, a genetic disorder of bilirubin metabolism found in a small percent of the population, can cause mild jaundice. Cirrhosis is the formation of fibrous tissue (fibrosis) in the place of liver cells that have died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and other forms of liver toxicity. Cirrhosis causes chronic liver failure. Primary liver cancer most commonly manifests as hepatocellular carcinoma or cholangiocarcinoma; rarer forms include angiosarcoma and hemangiosarcoma of the liver. (Many liver malignancies are secondary lesions that have metastasized from primary cancers in the gastrointestinal tract and other organs, such as the kidneys, lungs.) Primary biliary cirrhosis is a serious autoimmune disease of the bile capillaries. Primary sclerosing cholangitis is a serious chronic inflammatory disease of the bile duct, which is believed to be autoimmune in origin. Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic vein. Mechanisms Liver diseases can develop through several mechanisms: DNA damage One general mechanism, increased DNA damage, is shared by some of the major liver diseases, including infection by hepatitis B virus or hepatitis C virus, heavy alcohol consumption, and obesity.Viral infection by hepatitis B virus, or hepatitis C virus causes an increase of reactive oxygen species. The increase in intracellular reactive oxygen species is about 10,000-fold with chronic hepatitis B virus infection and 100,000-fold following hepatitis C virus infection. This increase in reactive oxygen species causes inflammation and more than 20 types of DNA damage. Oxidative DNA damage is mutagenic and also causes epigenetic alterations at the sites of DNA repair. Epigenetic alterations and mutations affect the cellular machinery that may cause the cell to replicate at a higher rate or result in the cell avoiding apoptosis, and thus contribute to liver disease. By the time accumulating epigenetic and mutational changes eventually cause hepatocellular carcinoma, epigenetic alterations appear to have an even larger role in carcinogenesis than mutations. Only one gene, TP53, is mutated in more than 20% of liver cancers while 41 genes each have hypermethylated promoters (repressing gene expression) in more than 20% of liver cancers.Alcohol consumption in excess causes a build-up of acetaldehyde. Acetaldehyde and free radicals generated by metabolizing alcohol induce DNA damage and oxidative stress. In addition, activation of neutrophils in alcoholic liver disease contributes to the pathogenesis of hepatocellular damage by releasing reactive oxygen species (which can damage DNA). The level of oxidative stress and acetaldehyde-induced DNA adducts due to alcohol consumption does not appear sufficient to cause increased mutagenesis. However, as reviewed by Nishida et al., alcohol exposure, causing oxidative DNA damage (which is repairable), can result in epigenetic alterations at the sites of DNA repair. Alcohol-induced epigenetic alterations of gene expression appear to lead to liver injury and ultimately carcinoma.Obesity is associated with a higher risk of primary liver cancer. As shown with mice, obese mice are prone to liver cancer, likely due to two factors. Obese mice have increased pro-inflammatory cytokines. Obese mice also have higher levels of deoxycholic acid, a product of bile acid alteration by certain gut microbes, and these microbes are increased with obesity. The excess deoxycholic acid causes DNA damage and inflammation in the liver, which, in turn, can lead to liver cancer. Other relevant aspects Several liver diseases are due to viral infection. Viral hepatitides such as Hepatitis B virus and Hepatitis C virus can be vertically transmitted during birth via contact with infected blood. According to a 2012 NICE publication, "about 85% of hepatitis B infections in newborns become chronic". In occult cases, Hepatitis B virus is present by hepatitis B virus DNA, but testing for HBsAg is negative. High consumption of alcohol can lead to several forms of liver disease including alcoholic hepatitis, alcoholic fatty liver disease, cirrhosis, and liver cancer. In the earlier stages of alcoholic liver disease, fat builds up in the livers cells due to increased creation of triglycerides and fatty acids and a decreased ability to break down fatty acids. Progression of the disease can lead to liver inflammation from the excess fat in the liver. Scarring in the liver often occurs as the body attempts to heal and extensive scarring can lead to the development of cirrhosis in more advanced stages of the disease. Approximately 3–10% of individuals with cirrhosis develop a form of liver cancer known as hepatocellular carcinoma. According to Tilg, et al., gut microbiome could very well have an effect, be involved in the pathophysiology, on the various types of liver disease which an individual may encounter. Insight into the exact causes and mechanisms mediating pathophysiology of the liver is quickly progressing due to the introduction new technological approaches like Single cell sequencing and kinome profiling Air pollutants Particulate matter or carbon black are common pollutants. They have a direct toxic effect on the liver; cause inflammation of liver caused by and thereby impact lipid metabolism and fatty liver disease; and can translocate from the lungs to the liver.Because particulate matter and carbon black are very diverse and each has different toxicodynamics, detailed mechanisms of translocation are not clear. Water-soluble fractions of particulate matter are the most important part of translocation to the liver, through extrapulmonary circulation. When particulate matter gets into the bloodstream, it combines with immune cells and stimulates innate immune responses. Pro-inflammatory cytokines are released and cause disease progression. Diagnosis A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products. serum proteins, serum albumin, serum globulin, alanine transaminase, aspartate transaminase, prothrombin time, partial thromboplastin time.Imaging tests such as transient elastography, ultrasound and magnetic resonance imaging can be used to show the liver tissue and the bile ducts. Liver biopsy can be performed to examine liver tissue to distinguish between various conditions; tests such as elastography may reduce the need for biopsy in some situations.In liver disease, prothrombin time is longer than usual. In addition, the amounts of both coagulation factors and anticoagulation factors are reduced as a diseased liver cannot productively synthesize them as it did when healthy. Nonetheless, there are two exceptions in this falling tendency: coagulation factor VIII and von Willebrand factor, a platelet adhesive protein. Both inversely rise in the setting of hepatic insufficiency, thanks to the drop of hepatic clearance and compensatory productions from other sites of the body. Fibrinolysis generally proceeds faster with acute liver failure and advanced stage liver disease, unlike chronic liver disease in which concentration of fibrinogen remains unchanged.A previously undiagnosed liver disease may become evident first after autopsy. Following are gross pathology images: Treatment Anti-viral medications are available to treat infections such as hepatitis B. Other conditions may be managed by slowing down disease progression, for example: By using steroid-based drugs in autoimmune hepatitis. Regularly removing a quantity of blood from a vein (venesection) in the iron overload condition, hemochromatosis. Wilson’s disease, a condition where copper builds up in the body, can be managed with drugs that bind copper, allowing it to be passed from the body in urine. In cholestatic liver disease, (where the flow of bile is affected due to cystic fibrosis) a medication called ursodeoxycholic acid may be given. See also Model for end-stage liver disease (MELD) References Further reading Friedman, Lawrence S.; Keeffe, Emmet B. (2011-08-03). Handbook of Liver Disease. Elsevier Health Sciences. ISBN 978-1455723164. == External links ==

Mittelschmerz

Mittelschmerz (German: "middle pain") is a colloquial term for "ovulation pain" or "midcycle pain". About 20% of women experience mittelschmerz, some every cycle, some intermittently. Signs and symptoms Mittelschmerz is characterized by lower abdominal and pelvic pain that occurs roughly midway through a womans menstrual cycle. The pain can appear suddenly and usually subsides within hours, although it may sometimes last two or three days. In some cases it can last up to the following cycle. In some women, the mittelschmerz is localized enough so that they can tell which of their two ovaries provided the egg in a given month. Because ovulation occurs on a random ovary each cycle, the pain may switch sides or stay on the same side from one cycle to another. Other ovulation symptoms Women may notice other physical symptoms associated with their mittelschmerz, during or near ovulation. The most common sign is the appearance of fertile cervical mucus in the days leading up to ovulation. Cervical mucus is one of the primary signs used by various fertility awareness methods. Other symptoms are sometimes called secondary fertility signs to distinguish from the three primary signs. Mid-cycle or ovulatory bleeding is thought to result from the sudden drop in estrogen that occurs just before ovulation. This drop in hormones can trigger withdrawal bleeding in the same way that switching from active to placebo birth control pills does. The rise in hormones that occurs after ovulation prevents such mid-cycle spotting from becoming as heavy or long lasting as a typical menstruation. Spotting is more common in longer cycles. A womans vulva may swell just prior to ovulation, especially the side on which ovulation will occur. One of the groin lymph nodes (on the side on which ovulation will occur) will swell to about the size of a pea, and may become tender. Causes Mittelschmerz is believed to have a variety of causes: Follicular swelling: The swelling of follicles in the ovaries prior to ovulation. While only one or two eggs mature to the point of being released, a number of follicles grow during the follicular phase of the menstrual cycle (non-dominant follicles atrophy prior to ovulation). Because follicles develop on both sides, this theory explains mittelschmerz that occurs simultaneously on both sides of the abdomen.Ovarian wall rupture: The ovaries have no openings; at ovulation the egg breaks through the ovarys wall. This may make ovulation itself painful for some women. Fallopian tube contraction: After ovulation, the fallopian tubes contract (similar to peristalsis of the esophagus), which may cause pain in some women. Smooth muscle cell contraction: At ovulation, this pain may be related to smooth muscle cell contraction in the ovary as well as in its ligaments. These contractions occur in response to an increased level of prostaglandin F2-alpha, itself mediated by the surge of luteinizing hormone (LH).Irritation: At the time of ovulation, blood or other fluid is released from the ruptured egg follicle. This fluid may cause irritation of the abdominal lining. Diagnosis Diagnosis of mittelschmerz is generally made if a woman is mid-cycle and a pelvic examination shows no abnormalities. If the pain is prolonged and/or severe, other diagnostic procedures such as an abdominal ultrasound may be performed to rule out other causes of abdominal pain. The pain of mittelschmerz is sometimes mistaken for appendicitis and is one of the differential diagnoses for appendicitis in women of child-bearing age. Treatment The pain is not harmful and does not signify the presence of disease. No treatment is usually necessary. Pain relievers (analgesics) such as NSAIDS (Non-steroidal anti inflammatories) may be needed in cases of prolonged or intense pain.Hormonal forms of contraception can be taken to prevent ovulation—and therefore ovulatory pain—but otherwise there is no known prevention. Usefulness Women charting with some form of fertility awareness may find mittelschmerz to be a helpful secondary sign in detecting ovulation. Because normal sperm life is up to five days, however, mittelschmerz alone does not provide sufficient advance warning to avoid pregnancy. Because other causes of minor abdominal pain are common, mittelschmerz alone also cannot be used to confirm the beginning of the post-ovulatory infertile period. References == External links ==

Intestinal capillariasis

Capillariasis is a disease in the group of helminthiasis diseases caused by the nematode Capillaria philippinensis. Symptoms and signs Symptoms in infested humans include watery diarrhea, abdominal pain, edema, weight loss, borborygmus (stomach growling), and depressed levels of potassium and albumin in the blood. In humans, the parasites damage the cells of the intestinal wall. This damage interferes with the absorption of nutrients and the maintenance of a proper electrolyte balance. Untreated C. philippinensis infestations are often fatal. Diagnosis Diagnosis usually involves finding the eggs and/or adults of C. philippinensis in stool samples. Prevention Prevention is as simple as avoiding eating small, whole, uncooked fish. However, in C. philippinensis endemic areas, such dietary habits are common and have been practiced for many generations. Treatment Anthelmintics such as mebendazole and albendazole have been reported to eliminate infestation of humans more effectively than thiabendazole. References == External links ==

Dural tear

Dural tear is a tear occurring in the dura mater of the brain. It is usually caused as a result of trauma or as a complication following surgery. Diagnosis In case of head injury, a dural tear is likely in case of a depressed skull fracture. A burr hole is made through the normal skull near the fractured portion, and Adsons elevator is introduced. Underlying dura is separated carefully from the overlying depressed bone fragments. The dura that is now visible is carefully examined to exclude any dural tear. Treatment The whole extent of the dural tear is exposed by removing the overlying skull. The ragged edges of the tear are excised. However, care should be taken not to excise too much dura as it may increase the chances for spread of infection into the subarachnoid space. Removing too much dura will also make it difficult to close the tear. If there is not much dural loss, interrupted sutures are made with non-absorbable material. In case of dural loss, the defect is closed using a transplant from fascia lata or pericranium given that there is not much contamination of the dura. In case of contamination, the defect is left alone and a primary suture is performed at a later date. If dural tear is associated with haemorrhage from dural vessels, they are coagulated using diathermy. This technique is preferred because the vessels are too small to be picked up by an artery forceps. Large vessels, if present, can be under-run with suture. When the dural tear is associated with a dural sinus hemorrhage, a graft of pericranium is used for a small tear and a muscle graft from temporalis is used for a large tear. The muscle graft is flattened by hammering before using it for grafting. If dural tear is associated with a brain injury, wide exposure of the wound is done to examine the extent of brain damage. All devitalized brain tissues are removed along with extravasated blood, foreign bodies and pieces of bone. All devitalized tissue and foreign bodies are removed by a combination of irrigation and suction. Following dural repair, skull deficit is treated by using moulded tantalum plates or acrylic inlays, three to six months after the head injury. == References ==

Flatulence

Flatulence, in humans, is the expulsion of gas from the intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swallowed environmental air, and hence flatus is not entirely generated in the stomach or bowels. The scientific study of this area of medicine is termed flatology.Flatus is brought to the rectum and pressurized by muscles in the intestines. It is normal to pass flatus ("to fart"), though volume and frequency vary greatly among individuals. It is also normal for intestinal gas to have a feculent or unpleasant odor, which may be intense. The noise commonly associated with flatulence ("blowing a raspberry") is produced by the anus and buttocks, which act together in a manner similar to that of an embouchure. Both the sound and odor are sources of embarrassment, annoyance or amusement (flatulence humor). There are several general symptoms related to intestinal gas: pain, bloating and abdominal distension, excessive flatus volume, excessive flatus odor, and gas incontinence. Furthermore, eructation (colloquially known as "burping") is sometimes included under the topic of flatulence. When excessive or malodorous, flatus can be a sign of a health disorder, such as irritable bowel syndrome, celiac disease or lactose intolerance. Terminology Non-medical definitions of the term include "the uncomfortable condition of having gas in the stomach and bowels", or "a state of excessive gas in the alimentary canal". These definitions highlight that many people consider "bloating", abdominal distension or increased volume of intestinal gas, to be synonymous with the term flatulence (although this is technically inaccurate). Colloquially, flatulence may be referred to as "farting", "pumping", "trumping", "blowing off", "pooting", "passing gas", "breaking wind", "backfiring", or simply (in American English) "gas" or (British English) "wind". Derived terms include vaginal flatulence, otherwise known as a queef. Signs and symptoms Generally speaking, there are four different types of complaints that relate to intestinal gas, which may present individually or in combination. Bloating and pain Patients may complain of bloating as abdominal distension, discomfort and pain from "trapped wind". In the past, functional bowel disorders such as irritable bowel syndrome that produced symptoms of bloating were attributed to increased production of intestinal gas. However, three significant pieces of evidence refute this theory. First, in normal subjects, even very high rates of gas infusion into the small intestine (30 mL/min) is tolerated without complaints of pain or bloating and harmlessly passed as flatus per rectum. Secondly, studies aiming to quantify the total volume of gas produced by patients with irritable bowel syndrome (some including gas emitted from the mouth by eructation) have consistently failed to demonstrate increased volumes compared to healthy subjects. The proportion of hydrogen produced may be increased in some patients with irritable bowel syndrome, but this does not affect the total volume. Thirdly, the volume of flatus produced by patients with irritable bowel syndrome who have pain and abdominal distension would be tolerated in normal subjects without any complaints of pain. Patients who complain of bloating frequently can be shown to have objective increases in abdominal girth, often increased throughout the day and then resolving during sleep. The increase in girth combined with the fact that the total volume of flatus is not increased led to studies aiming to image the distribution of intestinal gas in patients with bloating. They found that gas was not distributed normally in these patients: there was segmental gas pooling and focal distension. In conclusion, abdominal distension, pain and bloating symptoms are the result of abnormal intestinal gas dynamics rather than increased flatus production. Excessive volume The normal range of volumes of flatus in normal individuals varies hugely (476–1,491 mL/24 h). All intestinal gas is either swallowed environmental air, present intrinsically in foods and beverages, or the result of gut fermentation. Swallowing small amounts of air occurs while eating and drinking. This is emitted from the mouth by eructation (burping) and is normal. Excessive swallowing of environmental air is called aerophagia, and has been shown in a few case reports to be responsible for increased flatus volume. This is, however, considered a rare cause of increased flatus volume. Gases contained in food and beverages are likewise emitted largely through eructation, e.g., carbonated beverages. Endogenously produced intestinal gases make up 74 percent of flatus in normal subjects. The volume of gas produced is partially dependent upon the composition of the intestinal microbiota, which is normally very resistant to change, but is also very different in different individuals. Some patients are predisposed to increased endogenous gas production by virtue of their gut microbiota composition. The greatest concentration of gut bacteria is in the colon, while the small intestine is normally nearly sterile. Fermentation occurs when unabsorbed food residues arrive in the colon. Therefore, even more than the composition of the microbiota, diet is the primary factor that dictates the volume of flatus produced. Diets that aim to reduce the amount of undigested fermentable food residues arriving in the colon have been shown to significantly reduce the volume of flatus produced. Again, increased volume of intestinal gas will not cause bloating and pain in normal subjects. Abnormal intestinal gas dynamics will create pain, distension, and bloating, regardless of whether there is high or low total flatus volume. Odor Although flatus possesses an odor, this may be abnormally increased in some patients and cause social distress to the patient. Increased odor of flatus presents a distinct clinical issue from other complaints related to intestinal gas. Some patients may exhibit over-sensitivity to bad flatus odor, and in extreme forms, olfactory reference syndrome may be diagnosed. Recent informal research found a correlation between flatus odor and both loudness and humidity content. Incontinence of flatus "Gas incontinence" could be defined as loss of voluntary control over the passage of flatus. It is a recognised subtype of faecal incontinence, and is usually related to minor disruptions of the continence mechanisms. Some consider gas incontinence to be the first, sometimes only, symptom of faecal incontinence. Cause Intestinal gas is composed of varying quantities of exogenous sources and endogenous sources. The exogenous gases are swallowed (aerophagia) when eating or drinking or increased swallowing during times of excessive salivation (as might occur when nauseated or as the result of gastroesophageal reflux disease). The endogenous gases are produced either as a by-product of digesting certain types of food, or of incomplete digestion, as is the case during steatorrhea. Anything that causes food to be incompletely digested by the stomach or small intestine may cause flatulence when the material arrives in the large intestine, due to fermentation by yeast or prokaryotes normally or abnormally present in the gastrointestinal tract. Flatulence-producing foods are typically high in certain polysaccharides, especially oligosaccharides such as inulin. Those foods include beans, lentils, dairy products, onions, garlic, spring onions, leeks, turnips, swedes, radishes, sweet potatoes, potatoes, cashews, Jerusalem artichokes, oats, wheat, and yeast in breads. Cauliflower, broccoli, cabbage, Brussels sprouts and other cruciferous vegetables that belong to the genus Brassica are commonly reputed to not only increase flatulence, but to increase the pungency of the flatus.In beans, endogenous gases seem to arise from complex oligosaccharides (carbohydrates) that are particularly resistant to digestion by mammals, but are readily digestible by microorganisms (methane-producing archaea; Methanobrevibacter smithii) that inhabit the digestive tract. These oligosaccharides pass through the small intestine largely unchanged, and when they reach the large intestine, bacteria ferment them, producing copious amounts of flatus.When excessive or malodorous, flatus can be a sign of a health disorder, such as irritable bowel syndrome, celiac disease, non-celiac gluten sensitivity or lactose intolerance. It can also be caused by certain medicines, such as ibuprofen, laxatives, antifungal medicines or statins. Some infections, such as giardiasis, are also associated with flatulence.Interest in the causes of flatulence was spurred by high-altitude flight and human spaceflight; the low atmospheric pressure, confined conditions, and stresses peculiar to those endeavours were cause for concern. In the field of mountaineering, the phenomenon of high altitude flatus expulsion was first recorded over two hundred years ago. Mechanism Production, composition, and odor Flatus (intestinal gas) is mostly produced as a byproduct of bacterial fermentation in the gastrointestinal (GI) tract, especially the colon. There are reports of aerophagia (excessive air swallowing) causing excessive intestinal gas, but this is considered rare.Over 99% of the volume of flatus is composed of odorless gases. These include oxygen, nitrogen, carbon dioxide, hydrogen and methane. Nitrogen is not produced in the gut, but a component of environmental air. Patients who have excessive intestinal gas that is mostly composed of nitrogen have aerophagia. Hydrogen, carbon dioxide and methane are all produced in the gut and contribute 74% of the volume of flatus in normal subjects. Methane and hydrogen are flammable, and so flatus can be ignited if it contains adequate amounts of these components.Not all humans produce flatus that contains methane. For example, in one study of the faeces of nine adults, only five of the samples contained archaea capable of producing methane. The prevalence of methane over hydrogen in human flatus may correlate with obesity, constipation and irritable bowel syndrome, as archaea that oxidise hydrogen into methane promote the metabolisms ability to absorb fatty acids from food.The remaining trace (<1% volume) compounds contribute to the odor of flatus. Historically, compounds such as indole, skatole, ammonia and short chain fatty acids were thought to cause the odor of flatus. More recent evidence proves that the major contribution to the odor of flatus comes from a combination of volatile sulfur compounds. Hydrogen sulfide, methyl mercaptan (also known as methanethiol), dimethyl sulfide, dimethyl disulfide and dimethyl trisulfide are present in flatus. The benzopyrrole volatiles indole and skatole have an odor of mothballs, and therefore probably do not contribute greatly to the characteristic odor of flatus. In one study, hydrogen sulfide concentration was shown to correlate convincingly with perceived bad odor of flatus, followed by methyl mercaptan and dimethyl sulfide. This is supported by the fact that hydrogen sulfide may be the most abundant volatile sulfur compound present. These results were generated from subjects who were eating a diet high in pinto beans to stimulate flatus production. Others report that methyl mercaptan was the greatest contributor to the odor of flatus in patients not under any specific dietary alterations. It has now been demonstrated that methyl mercaptan, dimethyl sulfide, and hydrogen sulfide (described as decomposing vegetables, unpleasantly sweet/wild radish and rotten eggs respectively) are all present in human flatus in concentrations above their smell perception thresholds.It is recognized that increased dietary sulfur-containing amino acids significantly increases the odor of flatus. It is therefore likely that the odor of flatus is created by a combination of volatile sulfur compounds, with minimal contribution from non-sulfur volatiles. This odor can also be caused by the presence of large numbers of microflora bacteria or the presence of faeces in the rectum. Diets high in protein, especially sulfur-containing amino acids, have been demonstrated to significantly increase the odor of flatus. Volume and intestinal gas dynamics Normal flatus volume is 476 to 1491 mL per 24 hours. This variability between individuals is greatly dependent upon diet. Similarly, the number of flatus episodes per day is variable; the normal range is given as 8–20 per day. The volume of flatus associated with each flatulence event again varies (5–375 mL). The volume of the first flatulence upon waking in the morning is significantly larger than those during the day. This may be due to buildup of intestinal gas in the colon during sleep, the peak in peristaltic activity in the first few hours after waking or the strong prokinetic effect of rectal distension on the rate of transit of intestinal gas. It is now known that gas is moved along the gut independently of solids and liquids, and this transit is more efficient in the erect position compared to when supine. It is thought that large volumes of intestinal gas present low resistance, and can be propelled by subtle changes in gut tone, capacitance and proximal contraction and distal relaxation. This process is thought not to affect solid and liquid intra-lumenal contents.Researchers investigating the role of sensory nerve endings in the anal canal did not find them to be essential for retaining fluids in the anus, and instead speculate that their role may be to distinguish between flatus and faeces, thereby helping detect a need to defecate or to signal the end of defecation.The sound varies depending on the tightness of the sphincter muscle and velocity of the gas being propelled, as well as other factors, such as water and body fat. The auditory pitch (sound) of the flatulence outburst can also be affected by the anal embouchure. Among humans, flatulence occasionally happens accidentally, such as incidentally to coughing or sneezing or during orgasm; on other occasions, flatulence can be voluntarily elicited by tensing the rectum or "bearing down" on stomach or bowel muscles and subsequently relaxing the anal sphincter, resulting in the expulsion of flatus. Management Since problems involving intestinal gas present as different (but sometimes combined) complaints, the management is cause-related. Pain and bloating While not affecting the production of the gases themselves, surfactants (agents that lower surface tension) can reduce the disagreeable sensations associated with flatulence, by aiding the dissolution of the gases into liquid and solid faecal matter. Preparations containing simethicone reportedly operate by promoting the coalescence of smaller bubbles into larger ones more easily passed from the body, either by burping or flatulence. Such preparations do not decrease the total amount of gas generated in or passed from the colon, but make the bubbles larger and thereby allowing them to be passed more easily.Other drugs including prokinetics, lubiprostone, antibiotics and probiotics are also used to treat bloating in patients with functional bowel disorders such as irritable bowel syndrome, and there is some evidence that these measures may reduce symptoms.A flexible tube, inserted into the rectum, can be used to collect intestinal gas in a flatus bag. This method is occasionally needed in a hospital setting, when the patient is unable to pass gas normally. Volume One method of reducing the volume of flatus produced is dietary modification, reducing the amount of fermentable carbohydrates. This is the theory behind diets such as the low-FODMAP diet (a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, alcohols, and polyols).Most starches, including potatoes, corn, noodles, and wheat, produce gas as they are broken down in the large intestine. Intestinal gas can be reduced by fermenting the beans, and making them less gas-inducing, or by cooking them in the liquor from a previous batch. For example, the fermented bean product miso is less likely to produce as much intestinal gas. Some legumes also stand up to prolonged cooking, which can help break down the oligosaccharides into simple sugars. Fermentative lactic acid bacteria such as Lactobacillus casei and Lactobacillus plantarum reduce flatulence in the human intestinal tract.Probiotics (live yogurt, kefir, etc.) are reputed to reduce flatulence when used to restore balance to the normal intestinal flora. Live (bioactive) yogurt contains, among other lactic bacteria, Lactobacillus acidophilus, which may be useful in reducing flatulence. L. acidophilus may make the intestinal environment more acidic, supporting a natural balance of the fermentative processes. L. acidophilus is available in supplements. Prebiotics, which generally are non-digestible oligosaccharides, such as fructooligosaccharide, generally increase flatulence in a similar way as described for lactose intolerance. Digestive enzyme supplements may significantly reduce the amount of flatulence caused by some components of foods not being digested by the body and thereby promoting the action of microbes in the small and large intestines. It has been suggested that alpha-galactosidase enzymes, which can digest certain complex sugars, are effective in reducing the volume and frequency of flatus. The enzymes alpha-galactosidase, lactase, amylase, lipase, protease, cellulase, glucoamylase, invertase, malt diastase, pectinase, and bromelain are available, either individually or in combination blends, in commercial products. The antibiotic rifaximin, often used to treat diarrhea caused by the microorganism E. coli, may reduce both the production of intestinal gas and the frequency of flatus events. Odor Bismuth The odor created by flatulence is commonly treated with bismuth subgallate, available over-the-counter in the US as Devrom. Bismuth subgallate is commonly used by individuals who have had ostomy surgery, bariatric surgery, faecal incontinence and irritable bowel syndrome. Bismuth subsalicylate is a compound that binds hydrogen sulfide, and one study reported a dose of 524 mg four times a day for 3–7 days bismuth subsalicylate yielded a >95% reduction in faecal hydrogen sulfide release in both humans and rats. Another bismuth compound, bismuth subnitrate was also shown to bind to hydrogen sulfide. Another study showed that bismuth acted synergistically with various antibiotics to inhibit sulfate-reducing gut bacteria and sulfide production. Some authors proposed a theory that hydrogen sulfide was involved in the development of ulcerative colitis and that bismuth might be helpful in the management of this condition. However, bismuth administration in rats did not prevent them from developing ulcerative colitis despite reduced hydrogen sulfide production. Also, evidence suggests that colonic hydrogen sulfide is largely present in bound forms, probably sulfides of iron and other metals. Rarely, serious bismuth toxicity may occur with higher doses. Activated charcoal Despite being an ancient treatment for various digestive complaints, activated charcoal did not produce reduction in both the total flatus volume nor the release of sulfur-containing gasses, and there was no reduction in abdominal symptoms (after 0.52 g activated charcoal four times a day for one week). The authors suggested that saturation of charcoal binding sites during its passage through the gut was the reason for this. A further study concluded that activated charcoal (4 g) does not influence gas formation in vitro or in vivo. Other authors reported that activated charcoal was effective. A study in 8 dogs concluded activated charcoal (unknown oral dose) reduced hydrogen sulfide levels by 71%. In combination with yucca schidigera, and zinc acetate, this was increased to an 86% reduction in hydrogen sulfide, although flatus volume and number was unchanged. An early study reported activated charcoal (unknown oral dose) prevented a large increase in the number of flatus events and increased breath hydrogen concentrations that normally occur following a gas-producing meal.Garments and external devices In 1998, Chester "Buck" Weimer of Pueblo, Colorado, received a patent for the first undergarment that contained a replaceable charcoal filter. The undergarments are air-tight and provide a pocketed escape hole in which a charcoal filter can be inserted. In 2001 Weimer received the Ig Nobel Prize for Biology for his invention.A similar product was released in 2002, but rather than an entire undergarment, consumers are able to purchase an insert similar to a pantiliner that contains activated charcoal. The inventors, Myra and Brian Conant of Mililani, Hawaii, still claim on their website to have discovered the undergarment product in 2002 (four years after Chester Weimer filed for a patent for his product), but state that their tests "concluded" that they should release an insert instead. Incontinence Flatus incontinence where there is involuntary passage of gas, is a type of faecal incontinence, and is managed similarly. Society and culture In many cultures, flatulence in public is regarded as embarrassing, but, depending on context, may also be considered humorous. People will often strain to hold in the passing of gas when in polite company, or position themselves to silence or conceal the passing of gas. In other cultures, it may be no more embarrassing than coughing. While the act of passing flatus in some cultures is generally considered to be an unfortunate occurrence in public settings, flatulence may, in casual circumstances and especially among children, be used as either a humorous supplement to a joke ("pull my finger"), or as a comic activity in and of itself. The social acceptability of flatulence-based humour in entertainment and the mass media varies over the course of time and between cultures. A sufficient number of entertainers have performed using their flatus to lead to the coining of the term flatulist. The whoopee cushion is a joking device invented in the early 20th century for simulating a fart. In 2008, a farting application for the iPhone earned nearly $10,000 in one day.A farting game named Touch Wood was documented by John Gregory Bourke in the 1890s. It existed under the name of Safety in the 20th century in the U.S., and has been found being played in 2011.In January 2011, the Malawi Minister of Justice, George Chaponda, said that Air Fouling Legislation would make public "farting" illegal in his country. When reporting the story, the media satirised Chapondas statement with punning headlines. Later, the minister withdrew his statement. Environmental impact Flatulence is often blamed as a significant source of greenhouse gases, owing to the erroneous belief that the methane released by livestock is in the flatus. While livestock account for around 20% of global methane emissions, 90–95% of that is released by exhaling or burping. In cows, gas and burps are produced by methane-generating microbes called methanogens, that live inside the cows digestive system. Proposals for reducing methane production in cows include the feeding of supplements such as oregano and seaweed, and the genetic engineering of gut biome microbes to produce less methane.Since New Zealand produces large amounts of agricultural products, it is in the unique position of having high methane emissions from livestock compared to other greenhouse gas sources. The New Zealand government is a signatory to the Kyoto Protocol and therefore attempts are being made to reduce greenhouse emissions. To achieve this, an agricultural emissions research levy was proposed, which promptly became known as a "fart tax" or "flatulence tax". It encountered opposition from farmers, farming lobby groups and opposition politicians. Entertainment Historical comment on the ability to fart at will is observed as early as Saint Augustines The City of God (5th century A.D.). Augustine mentions men who "have such command of their bowels, that they can break wind continuously at will, so as to produce the effect of singing". Intentional passing of gas and its use as entertainment for others appear to have been somewhat well known in pre-modern Europe, according to mentions of it in medieval and later literature, including Rabelais. Le Pétomane ("the Fartomaniac") was a famous French performer in the 19th century who, as well as many professional farters before him, did flatulence impressions and held shows. The performer Mr. Methane carries on le Pétomanes tradition today. Also, a 2002 fiction film Thunderpants revolves around a boy named Patrick Smash who has an ongoing flatulence problem from the time of his birth.Since the 1970s, farting has increasingly been featured in film, especially comedies such as Blazing Saddles and Scooby-Doo. Religion In Islam, flatulence, if audible or odorous, invalidates wudu (ritual purity). Personal experiences People find other peoples flatus unpleasant, but are unfazed by, and may even enjoy, the scent of their own. While there has been little research carried out upon the subject, some speculative guesses have been made as to why this might be so. For example, one explanation for this phenomenon is that people are very familiar with the scent of their own flatus, and that survival in nature may depend on the detection of and reaction to foreign scents. See also References Citations General and cited references Allen, V. (2007). On Farting: Language and Laughter in the Middle Ages. Palgrave MacMillan. ISBN 978-0-312-23493-5. Bolin, T. D. & Stanton, R. (1997). Wind Breaks. Allen & Unwin. ISBN 978-1-86448-321-5. Dawson, Jim (1999). Who Cut the Cheese?: A Cultural History of the Fart. Ten Speed Press. ISBN 1-58008-011-1. Dawson, Jim (2006). Blame it on the Dog: A Modern History of the Fart. Ten Speed Press. ISBN 1-58008-751-5. Franklin, Benjamin (2003). Japikse, Carl (ed.). Fart Proudly ((Reprint) ed.). Frog Ltd/Blue Snake. ISBN 1-58394-079-0. Persels, J., & Ganim, R. (2004). Fecal Matters in Early Modern Literature and Art: Studies in Scatology. (Chap. 1: "The Honorable Art of Farting in Continental Renaissance"). ISBN 0-7546-4116-3. von Schmausen, D. (2002). Official Rules, New World Odor International Freestyle Farting Championship. LULU. ISBN 1435709195. External links The Merck Manual of Diagnosis and Therapy, Gas Dictionary of Fart Slang Invisible College of Experimental Flatology

Worry

Worry refers to the thoughts, images, emotions, and actions of a negative nature in a repetitive, uncontrollable manner that results from a proactive cognitive risk analysis made to avoid or solve anticipated potential threats and their potential consequences. Introduction Psychologically, worry is part of Perseverative Cognition (a collective term for continuous thinking about negative events in the past or in the future). As an emotion "worry" is experienced from anxiety or concern about a real or imagined issue, often personal issues such as health or finances, or external broader issues such as environmental pollution, social structure or technological change. It is a natural response to anticipated future problems. Excessive worry is a primary diagnostic feature of generalized anxiety disorder, but also is pervasive in other psychological disorders, like schizophrenia. Most people experience short-lived periods of worry in their lives without incident; indeed, a mild amount of worrying have positive effects, if it prompts people to take precautions (e.g., fastening their seat belt or buying insurance) or avoid risky behaviors (e.g., angering dangerous animals, or binge drinking), but with excessive worrisome people they overestimate future dangers in their assessments and in its extremities tend to magnify the situation as a dead end which results stress. Overestimation happens because analytic resources are a combination of external locus of control, personal experience and belief fallacies. Chronically worried individuals are also more likely to lack confidence in their problem solving ability, perceive problems as threats, become easily frustrated when dealing with a problem, and are pessimistic about the outcome of problem-solving efforts.Seriously anxious people find it difficult to control their worry and typically experience symptoms like restlessness, fatigue, difficulty in concentrating, irritability, muscle tension and sleep disturbance. Theories Avoidance model The avoidance model of worry (AMW) theorizes that worry is a verbal linguistic, thought based activity, which arises as an attempt to inhibit vivid mental imagery and associated somatic and emotional activation. This inhibition precludes the emotional processing of fear that is theoretically necessary for successful habituation and extinction of feared stimuli. Worry is reinforced as a coping technique due to the fact that most worries never actually occur, leaving the worrier with a feeling of having successfully controlled the feared situation, without the unpleasant sensations associated with exposure. Noteworthy, studies also show that visual worry, i.e. worrying that occurs in visual modality, is also associated with increased anxiety and other psychopathology symptoms. Cognitive model This model explains pathological worry to be an interaction between involuntary (bottom-up) processes, such as habitual biases in attention and interpretation favoring threat content, and voluntary (top-down) processes, such as attentional control. Emotional processing biases influence the probability of threat representations into the awareness as intruding negative or positive thoughts. At a pre-conscious level, these processes influence the competition among mental representations in which some correspond to the assertive power of worry with impaired cognitive process and others to the preventive power of worry with attentional control or exhaustive vigilance. The biases determine threatening degree and nature of worry content the worrier attempts to resolve the perceived threat and the redirection of anticipations, responses and coping in such situations.There are some who respond to mental representations in an uncertain or ambiguous state in regard to the stressful or upsetting event. In this state the worrier is held in a perpetual state of worry. This is because availability of an overwhelming number(maybe 2 or 3, depending upon the worry-prone individual) of possibilities of outcomes which can be generated, it puts the worrier in a threatening crisis and they focus their attentional control voluntarily on the potential negative outcomes, whereas others engage in a constructive problem solving manner and in a benign approach rather than to engage with heightened anticipation on the possible negative outcome. Philosophical perspectives Greek thinkers such as stoic philosopher Epictetus and Seneca advised against worry. Albert Ellis, the creator of Rational Emotive Behavior Therapy, was inspired by the Stoics’ therapeutic ideas. Religious perspectives The biblical word used in Hebrew for worry (Hebrew: דָּאַג, daag) regards worry as a combined form of fear and sorrow which affects nephesh, the totality of our being. The bible takes a fortitude-strengthening approach regarding worrying e.g. Psalm 94: In the multitude of my anxieties within me, your comforts delight my soul.In the New Testament, the Gospel of Matthew encourages: And can any of you by worrying add a single hour to your span of life? ... So do not worry about tomorrow, for tomorrow will bring worries of its own. Today’s trouble is enough for today.The Greek word used for worry in Matthew is merimnaō, which means to be anxious about, or to be troubled with cares. St. Paul writes to the Philippian church, "There is no need to worry" and in the pastoral epistles, 2 Timothy 1:7 emboldens: For God did not give us a spirit of cowardice, but rather a spirit of power and of love and of self-discipline.Similarly James 1:2-4 motivates to face trials of any kind with joy, because they produce endurance (strength and courage). Further Saint Peter reveals his understanding of healthy living in Second Peter 1:3,5–7: We have a sure hope ... this is a cause of great joy for us.A late Indian spiritual teacher Meher Baba stated that worry is caused by desires and can be overcome through detachment: Worry is the product of feverish imagination working under the stimulus of desires ... (It) is a necessary resultant of attachment to the past or to the anticipated future, and it always persists in some form or other until the mind is completely detached from everything. Management The worry system is activated from exposure to a potential triggering event, traumatic experience or vulnerability, this brings worrisome thoughts and feelings which bring about physical stress reactions and response to avoid worrisome behavior, to ensure allostasis. But under the crisis this activity feeds back into the first worrisome thoughts and feelings which generates and strengthens the vicious worry cycle. Relaxation, risk assessment, worry exposure and behavior prevention have been proven effective in curbing the excessive worry, a chief feature of generalized anxiety disorder. Cognitive behavioral techniques hasnt branched out enough to address the problem holistically but therapy can control or diminish worry. See also References Further reading Kate Sweeny; Michael D. Dooley (18 April 2017). "The surprising upsides of worry". Social and Personality Psychology Compass. 11 (4): e12311. doi:10.1111/spc3.12311. External links Current theoretical models of generalized anxiety disorder (GAD): Conceptual review and treatment implications

Neisseria meningitidis

Neisseria meningitidis, often referred to as meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a coccus because it is round, and more specifically a diplococcus because of its tendency to form pairs. About 10% of adults are carriers of the bacteria in their nasopharynx. As an exclusively human pathogen, it is the main cause of bacterial meningitis in children and young adults, causing developmental impairment and death in about 10% of cases. It causes the only form of bacterial meningitis known to occur epidemically, mainly in Africa and Asia. It occurs worldwide in both epidemic and endemic form.N. meningitidis is spread through saliva and respiratory secretions during coughing, sneezing, kissing, chewing on toys and through sharing a source of fresh water. It has also been reported to be transmitted through oral sex and cause urethritis in men. It infects its host cells by sticking to them with long thin extensions called pili and the surface-exposed proteins Opa and Opc and has several virulence factors. Signs and symptoms Meningococcus can cause meningitis and other forms of meningococcal disease. It initially produces general symptoms like fatigue, fever, and headache and can rapidly progress to neck stiffness, coma and death in 10% of cases. Petechiae occur in about 50% of cases. Chance of survival is highly correlated with blood cortisol levels, with lower levels prior to steroid administration corresponding with increased patient mortality. Symptoms of meningococcal meningitis are easily confused with those caused by other bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae. Suspicion of meningitis is a medical emergency and immediate medical assessment is recommended. Current guidance in the United Kingdom is that if a case of meningococcal meningitis or septicaemia (infection of the blood) is suspected, intravenous antibiotics should be given and the ill person admitted to the hospital. This means that laboratory tests may be less likely to confirm the presence of Neisseria meningitidis as the antibiotics will dramatically lower the number of bacteria in the body. The UK guidance is based on the idea that the reduced ability to identify the bacteria is outweighed by reduced chance of death. Septicaemia caused by Neisseria meningitidis has received much less public attention than meningococcal meningitis even though septicaemia has been linked to infant deaths. Meningococcal septicaemia typically causes a purpuric rash, that does not lose its color when pressed with a glass slide ("non-blanching") and does not cause the classical symptoms of meningitis. This means the condition may be ignored by those not aware of the significance of the rash. Septicaemia carries an approximate 50% mortality rate over a few hours from initial onset. Other severe complications include Waterhouse–Friderichsen syndrome, a massive, usually bilateral, hemorrhage into the adrenal glands caused by fulminant meningococcemia, adrenal insufficiency, and disseminated intravascular coagulation.Not all instances of a purpura-like rash are due to meningococcal septicaemia; other possible causes, such as idiopathic thrombocytopenic purpura (ITP; a platelet disorder) and Henoch–Schönlein purpura, also need prompt investigation. Microbiology N. meningitidis is a Gram-negative diplococcus since it has an outer and inner membranes with a thin layer of peptidoglycan in between. It is 0.6–1.0 micrometers in size. It tests positive for the enzyme cytochrome c oxidase. Habitat N. meningitidis is a part of the normal nonpathogenic flora in the nasopharynx of up to 8–25% of adults. It colonizes and infects only humans, and has never been isolated from other animals. This is thought to result from the bacteriums inability to get iron from sources other than human transferrin and lactoferrin. Subtypes Disease-causing strains are classified according to the antigenic structure of their polysaccharide capsule. Serotype distribution varies markedly around the world. Among the 13 identified capsular types of N. meningitidis, six (A, B, C, W135, X, and Y) account for most disease cases worldwide. Type A has been the most prevalent in Africa and Asia, but is rare/practically absent in North America. In the United States, serogroup B is the predominant cause of disease and mortality, followed by serogroup C. The multiple subtypes have hindered development of a universal vaccine for meningococcal disease. Pathogenesis Virulence Lipooligosaccharide (LOS) is a component of the outer membrane of N. meningitidis. This acts as an endotoxin and is responsible for septic shock and hemorrhage due to the destruction of red blood cells. Other virulence factors include a polysaccharide capsule which prevents host phagocytosis and aids in evasion of the host immune response. Adhesion is another key virulence strategy to successfully invade host cell. There are several known proteins that are involved in adhesion and invasion, or mediate interactions with specific host cell receptors. These include the Type IV pilin adhesin which mediates attachment of the bacterium to the epithelial cells of the nasopharynx, surface-exposed Opa and Opc proteins which mediate interactions with specific host cell receptors, and NadA which is involved in adhesion.Pathogenic meningococci that have invaded into the bloodstream must be able to survive in the new niche, this is facilitated by acquisition and utilisation of iron (FetA and Hmbr), resisting intracellular oxidative killing by producing catalase and superoxide dismutase and ability to avoid complement mediated killing (fHbp). Meningococci produce an IgA protease, an enzyme that cleaves IgA class antibodies and thus allows the bacteria to evade a subclass of the humoral immune system. A hypervirulent strain was discovered in China. Its impact is yet to be determined. Complement inhibition Factor H binding protein (fHbp) that is exhibited in N. meningitidis and some commensal species is the main inhibitor of the alternative complement pathway. fHbp protects meningococci from complement-mediated death in human serum experiments, but has also been shown to protect meningococci from antimicrobial peptides in vitro. Factor H binding protein is key to the pathogenesis of N. meningitidis, and is, therefore, important as a potential vaccine candidate. Porins are also an important factor for complement inhibition for both pathogenic and commensal species. Porins are important for nutrient acquisition. Porins are also recognized by TLR2, they bind complement factors (C3b, C4b, factor H, and C4bp (complement factor 4b-binding protein)). Cooperation with pili for CR3-mediated internalization is another function of porins. Ability to translocate into host cells and modulate reactive oxygen species production and apoptosis is made possible by porins, as well. Strains of the same species can express different porins. Genome At least 8 complete genomes of Neisseria meningitidis strains have been determined which encode about 2,100 to 2,500 proteins.The genome of strain MC58 (serogroup B) has 2,272,351-base pairs. When sequenced in 2000, it was found to contain 2158 open reading frames (ORFs). Of these, a biological function was predicted for 1158 (53.7%). There were three major islands of horizontal DNA transfer found. Two encode proteins involved in pathogenicity. The third island only codes for hypothetical proteins. They also found more genes that undergo phase variation than any pathogen then known. Phase variation is a mechanism that helps the pathogen to evade the immune system of the host.The genome size of strain H44/76 is 2.18 Mb, and encodes 2,480 open reading frames (ORFs), compared to 2.27 Mb and 2,465 ORFs for MC58. Both strains have a GC content of 51.5%. A comparison with MC58 showed that four genes are uniquely present in H44/76 and nine genes are only present in MC58. Of all ORFs in H44/76, 2,317 (93%) show more than 99% sequence identity.The complete genome sequence of strain NMA510612 (serogroup A) consists of one circular chromosome with a size of 2,188,020 bp, and the average GC content is 51.5%. The chromosome is predicted to possess 4 rRNA operons, 163 insertion elements (IS), 59 tRNAs, and 2,462 ORFs.There is a public database available for N. meningitidis core genome multilocus sequence typing (cMILST). Available at: https://pubmlst.org/bigsdb?db=pubmlst_neisseria_seqdef Genetic transformation Genetic transformation is the process by which a recipient bacterial cell takes up DNA from a neighboring cell and integrates this DNA into the recipients genome by recombination. In N. meningitidis, DNA transformation requires the presence of short DNA sequences (9–10 mers residing in coding regions) of the donor DNA. These sequences are called DNA uptake sequences (DUSs). Specific recognition of these sequences is mediated by a type IV pilin. In N. meningitidis DUSs occur at a significantly higher density in genes involved in DNA repair and recombination (as well as in restriction-modification and replication) than in other annotated gene groups. The over-representation of DUS in DNA repair and recombination genes may reflect the benefit of maintaining the integrity of the DNA repair and recombination machinery by preferentially taking up genome maintenance genes, that could replace their damaged counterparts in the recipient cell.N. meningititis colonizes the nasopharyngeal mucosa, which is rich in macrophages. Upon their activation, macrophages produce superoxide (O2−) and hydrogen peroxide (H2O2). Thus N. meningitidis is likely to encounter oxidative stress during its life cycle. Consequently, an important benefit of genetic transformation to N. meningitidis may be the maintenance of the recombination and repair machinery of the cell that removes oxidative DNA damages such as those caused by reactive oxygen. This is consistent with the more general idea that transformation benefits bacterial pathogens by facilitating repair of DNA damages produced by the oxidative defenses of the host during infection.Meningococci population is extensively diverse genetically, this is due to horizontal gene transfers while in the nasophanrynx. Gene transfer can occur within and between genomes of Neisseria species, and it is the main mechanism of acquiring new traits. This is facilitated by the natural competence of the meningococci to take up foreign DNA. The commensal species of Neisseria can act as a reservoir of genes that can be acquired, for example, this is how capsule switching can occur as a means of hiding from the immune system. An invasive N. meningitidis strain of serogroup C broke out in Nigeria in 2013 - the strain was a new sequence type, ST-10217 determined by multilocus sequence typing. It was determined that a commensal strain of N. meningitidis acquired an 8-kb prophage, the meningococcal disease-associated island (MDAΦ), previously associated with hyper-invasiveness; and the full serogroup C capsule operon, thus becoming a hypervirulent strain. This illustrates how hypervirulent strains can arise from non-pathgenic strains due to the high propensity of gene transfers and DNA uptake by N. meningitidis. Diagnosis A small amount of cerebrospinal fluid (CSF) is sent to the laboratory as soon as possible for analysis. The diagnosis is suspected, when Gram-negative diplococci are seen on Gram stain of a centrifuged sample of CSF; sometimes they are located inside white blood cells. The microscopic identification takes around 1–2 hours after specimen arrival in the laboratory.The gold standard of diagnosis is microbiological isolation of N. meningitidis by growth from a sterile body fluid, which could be CSF or blood. Diagnosis is confirmed when the organism has grown, most often on a chocolate agar plate, but also on Thayer-Martin agar. To differentiate any bacterial growth from other species a small amount of a bacterial colony is tested for oxidase, catalase for which all clinically relevant Neisseria show a positive reaction, and the carbohydrates maltose, sucrose, and glucose, in which N. meningitidis will ferment that is, utilize the glucose and maltose. Finally, serology determines the subgroup of the N. meningitidis, which is important for epidemiological surveillance purposes; this may often only be done in specialized laboratories. The above tests take a minimum of 48–72 hours turnaround time for growing the organism, and up to a week more for serotyping. Growth can and often does fail, either because antibiotics have been given preemptively, or because specimens have been inappropriately transported, as the organism is extremely susceptible to antibiotics and fastidious in its temperature, CO2 and growth medium requirements. Polymerase chain reaction (PCR) tests where available, mostly in industrialized countries, have been increasingly used; PCR can rapidly identify the organism, and works even after antibiotics have been given. Prevention All recent contacts of the infected patient over the 7 days before onset should receive medication to prevent them from contracting the infection. This especially includes young children and their child caregivers or nursery-school contacts, as well as anyone who had direct exposure to the patient through kissing, sharing utensils, or medical interventions such as mouth-to-mouth resuscitation. Anyone who frequently ate, slept or stayed at the patients home during the 7 days before the onset of symptom, or those who sat beside the patient on an airplane flight or classroom for 8 hours or longer, should also receive chemoprophylaxis. The agent of choice is usually oral rifampicin for a few days.Receiving a dose of the Meningococcal vaccine before traveling to a country in the "meningitis belt" or having a booster meningitis vaccine, normally five years apart could prevent someone from getting an infection from the pathogen. Vaccination United States A number of vaccines are available in the U.S. to prevent meningococcal disease. Some of the vaccines cover serogroup B, while others cover A, C, W, and Y. The Centers for Disease Control and Prevention (CDC) recommends all teenagers receive MenACWY vaccine and booster, with optional MenB. MenACWY and MenB are also recommended for people of other ages with various medical conditions and social risk factors.A meningococcal polysaccharide vaccine (MPSV4) has been available since the 1970s and is the only meningococcal vaccine licensed for people older than 55. MPSV4 may be used in people 2–55 years old if the MCV4 vaccines are not available or contraindicated. Two meningococcal conjugate vaccines (MCV4) are licensed for use in the U.S. The first conjugate vaccine was licensed in 2005, the second in 2010. Conjugate vaccines are the preferred vaccine for people 2 through 55 years of age. It is indicated in those with impaired immunity, such as nephrotic syndrome or splenectomy. In June 2012, the U.S. Food and Drug Administration (FDA) approved a combination vaccine against two types of meningococcal diseases and Hib disease for infants and children 6 weeks to 18 months old. The vaccine, Menhibrix, was designed to prevent disease caused by Neisseria meningitidis serogroups C and Y, and Haemophilus influenzae type b (Hib). It was the first meningococcal vaccine that could be given to infants as young as six weeks old.In October 2014 the FDA approved the first vaccine effective against serogroup B, named Trumenba, for use in 10- to 25-year-old individuals. Africa In 2010, the Meningitis Vaccine Project introduced a vaccine called MenAfriVac in the African meningitis belt. It was made by generic drug maker Serum Institute of India and cost 50 U.S. cents per injection. Beginning in Burkina Faso in 2010, it has been given to 215 million people across Benin, Cameroon, Chad, Ivory Coast, Ethiopia, Ghana, Mali, Niger, Mauritania, Nigeria, Senegal, Sudan, Togo and Gambia. The vaccination campaign has resulted in near-elimination of serogroup A meningitis from the participating countries. Treatment Persons with confirmed N. meningitidis infection should be hospitalized immediately for treatment with antibiotics. Because meningococcal disease can disseminate very rapidly, a single dose of intramuscular antibiotic is often given at the earliest possible opportunity, even before hospitalization, if disease symptoms look suspicious enough. Third-generation cephalosporin antibiotics (i.e. cefotaxime, ceftriaxone) should be used to treat a suspected or culture-proven meningococcal infection before antibiotic susceptibility results are available. Clinical practice guidelines endorse empirical treatment in the event a lumbar puncture to collect cerebrospinal fluid (CSF) for laboratory testing cannot first be performed. Antibiotic treatment may affect the results of microbiology tests, but a diagnosis may be made on the basis of blood-cultures and clinical examination. Epidemiology N. meningitidis is a major cause of illness, developmental impairment and death during childhood in industrialized countries and has been responsible for epidemics in Africa and in Asia. Every year, about 2,500 to 3,500 people become infected with N. meningitidis in the US, with a frequency of about 1 in 100,000. Children younger than 5 years are at greatest risk, followed by teenagers of high school age. Rates in the African meningitis belt were as high as 1 in 1,000 to 1 in 100 before introduction of a vaccine in 2010. The incidence of meningococcal disease is highest among infants (children younger than 1-year-old) whose immune system is relatively immature. In industrialized countries there is a second peak of incidence in young adults, who are congregating closely, living in dormitories or smoking. Vaccine development is ongoing.It is spread through saliva and other respiratory secretions during coughing, sneezing, kissing, and chewing on toys. Inhalation of respiratory droplets from a carrier which may be someone who is themselves in the early stages of disease can transmit the bacteria. Close contact with a carrier is the predominant risk factor. Other risk factors include a weakened general or local immune response, such as a recent upper respiratory infection, smoking, and complement deficiency. The incubation period is short, from 2 to 10 days. In susceptible individuals, N. meningitidis may invade the bloodstream and cause a systemic infection, sepsis, disseminated intravascular coagulation, breakdown of circulation, and septic shock. History In 1884 Ettore Marchiafava and Angelo Celli first observed the bacterium inside cells in the cerebral spinal fluid (CSF). In 1887 Anton Weichselbaum isolated the bacterium from the CSF of patients with bacterial meningitis. He named the bacterium Diplococcus intracellularis meningitidis. Biotechnology Components from Neisseria meningitidis are being harnessed in biotechnology. Its Cas9 enzyme is a useful tool in CRISPR gene editing because the enzyme is small and has distinct targeting features to the commonly used enzyme from Streptococcus pyogenes. The cell-surface protein FrpC from Neisseria meningitidis has been engineered to allow covalent coupling between proteins, because it generates a reactive anhydride when exposed to calcium. The bacterium also expresses unique enzymes able to cleave IgA antibodies. See also DNA uptake sequence DNA taken up by Neisseria NmVac4-A/C/Y/W-135 polysaccharide vaccine Sara Branham Matthews microbiologist Shwartzman phenomenon Sepsis References External links "Neisseria meningitidis". NCBI Taxonomy Browser. 487. Type strain of Neisseria meningitidis at BacDive - the Bacterial Diversity Metadatabase

Clonorchiasis

Clonorchiasis is an infectious disease caused by the Chinese liver fluke (Clonorchis sinensis) and two related species. Clonorchiasis is a known risk factor for the development of cholangiocarcinoma, a neoplasm of the biliary system.Symptoms of opisthorchiasis caused by Opisthorchis viverrini and by O. felineus are indistinguishable from clonorchiasis caused by Clonorchis sinensis, leading some to argue that the disease by these three parasites should be referred to collectively as clonorchiasis. Signs and symptoms Cause Clonorchiasis sinensis is a trematode (fluke) which is part of the phylum Platyhelminthes. The parasitic worm is as long as 10 to 25 mm and lives in the bile ducts of the liver. It is a hermaphroditic fluke that requires two intermediate hosts. The eggs of the worms are passed in fecal matter into a body of water and are then ingested by mollusks. The water snail is the first intermediate host, in which a miracidium (an embryonated egg discharged in stool) goes through its developmental stages (sporocyst, rediae and cercariae). Freshwater fish are a second intermediate host for the parasitic worm. They become infected when the larva (cercaria) of the worm leaves the snail and penetrates the flesh of the fish. Humans then become infected by eating infected fish that has been undercooked, smoked, pickled, or salted, and from there the cycle repeats. Clonorchiasis is endemic in the Far East, especially in Korea, Japan, Taiwan, and Southern China. Clonorchiasis has been reported in areas to which it is not endemic (including the United States). In such cases, the infection follows the ingestion of undercooked or pickled freshwater fish imported from one of the endemic areas and containing metacercariae. Diagnosis Adult C. sinensis worms can inhabit the bile ducts of humans for 20–25 years without any clear clinical symptoms. This, in addition to the nonspecific symptoms infected persons may develop, can lead to missed diagnoses.Patients are diagnosed when C. sinensis eggs are found in stools. The formalin-ether concentration technique (FECT) method of stool examination is most effective at diagnosing light cases of infection, while the Kato-Katz (KK) method is more suitable for the diagnosing of persons with clonorchiasis. Serological methods that use enzyme-linked immunosorbent assay (ELISA) can help differentiate the eggs of C. sinensis from other flukes. Treatment Praziquantel is the treatment of choice for clonorchiasis. References == External links ==

Tuberculous meningitis

Tuberculous meningitis, also known as TB meningitis or tubercular meningitis, is a specific type of bacterial meningitis caused by the Mycobacterium tuberculosis infection of the meninges—the system of membranes which envelop the central nervous system. Signs and symptoms Fever and headache are the cardinal features; confusion is a late feature and coma bears a poor prognosis. Meningism is absent in a fifth of patients with TB meningitis. Patients may also have focal neurological deficits. Causes Mycobacterium tuberculosis of the meninges is the cardinal feature and the inflammation is concentrated towards the base of the brain. When the inflammation is in the brain stem subarachnoid area, cranial nerve roots may be affected. The symptoms will mimic those of space-occupying lesions.Blood-borne spread certainly occurs, presumably by crossing the blood–brain barrier; but a proportion of patients may get TB meningitis from rupture of a cortical focus in the brain; an even smaller proportion get it from rupture of a bony focus in the spine. Pathophysiology The pathophysiology of tuberculous meningitis involves bacterial invasion of the brain parenchyma meninges or cortex, causing the formation of small subpial foci. These foci, termed Rich foci, are necrotic and expand as the colonies within them multiply. Tubercle (focal) rupture in the subarachnoid space causes meningitis. Diagnosis Diagnosis of TB meningitis is made by analysing cerebrospinal fluid collected by lumbar puncture. When collecting CSF for suspected TB meningitis, a minimum of 1ml of fluid should be taken (preferably 5 to 10ml). The CSF usually has a high protein, low glucose and a raised number of lymphocytes. Acid-fast bacilli are sometimes seen on a CSF smear, but more commonly, M. tuberculosis is grown in culture. A spiderweb clot in the collected CSF is characteristic of TB meningitis, but is a rare finding. ELISPOT testing is not useful for the diagnosis of acute TB meningitis and is often false negative, but may paradoxically become positive after treatment has started, which helps to confirm the diagnosis. Nucleic acid amplification tests (NAAT) This is a group of tests that use polymerase chain reaction (PCR) to detect mycobacterial nucleic acid. These test vary in which nucleic acid sequence they detect and vary in their accuracy. The two most common commercially available tests are the amplified mycobacterium tuberculosis direct test (MTD, Gen-Probe) and Amplicor. In 2007, review concluded that for diagnosing tuberculous meningitis "Individually, the AMTD test appears to perform the best (sensitivity 74% and specificity 98%)", they found the pooled prevalence of TB meningitis to be 29%. Treatment The treatment of TB meningitis is isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by isoniazid and rifampicin alone for a further ten months. Steroids help reduce the risk of death in those without HIV. Steroids can be used in the first six weeks of treatment, A few people may require immunomodulatory agents such as thalidomide. Hydrocephalus occurs as a complication in about a third of people with TB meningitis. The addition of aspirin may reduce or delay mortality, possibly by reducing complications such as infarcts. References == External links ==

Major depressive disorder

Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introduced by a group of US clinicians in the mid-1970s, the term was adopted by the American Psychiatric Association for this symptom cluster under mood disorders in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and has become widely used since. The diagnosis of major depressive disorder is based on the persons reported experiences, behavior reported by relatives or friends, and a mental status examination. There is no laboratory test for the disorder, but testing may be done to rule out physical conditions that can cause similar symptoms. The most common time of onset is in a persons 20s, with females affected about twice as often as males. The course of the disorder varies widely, from one episode lasting months to a lifelong disorder with recurrent major depressive episodes. Those with major depressive disorder are typically treated with psychotherapy and antidepressant medication. Medication appears to be effective, but the effect may be significant only in the most severely depressed. Hospitalization (which may be involuntary) may be necessary in cases with associated self-neglect or a significant risk of harm to self or others. Electroconvulsive therapy (ECT) may be considered if other measures are not effective.Major depressive disorder is believed to be caused by a combination of genetic, environmental, and psychological factors, with about 40% of the risk being genetic. Risk factors include a family history of the condition, major life changes, certain medications, chronic health problems, and substance use disorders. It can negatively affect a persons personal life, work life, or education, and cause issues with a persons sleeping habits, eating habits, and general health. Major depressive disorder affected approximately 163 million people (2% of the worlds population) in 2017. The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. Lifetime rates are higher in the developed world (15%) compared to the developing world (11%). The disorder causes the second-most years lived with disability, after lower back pain. Symptoms and signs Major depression significantly affects a persons family and personal relationships, work or school life, sleeping and eating habits, and general health. A person having a major depressive episode usually exhibits a low mood, which pervades all aspects of life, and an inability to experience pleasure in previously enjoyable activities. Depressed people may be preoccupied with—or ruminate over—thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness. Other symptoms of depression include poor concentration and memory, withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. Insomnia is common; in the typical pattern, a person wakes very early and cannot get back to sleep. Hypersomnia, or oversleeping, can also happen. Some antidepressants may also cause insomnia due to their stimulating effect. In severe cases, depressed people may have psychotic symptoms. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant. People who have had previous episodes with psychotic symptoms are more likely to have them with future episodes.A depressed person may report multiple physical symptoms such as fatigue, headaches, or digestive problems; physical complaints are the most common presenting problem in developing countries, according to the World Health Organizations criteria for depression. Appetite often decreases, resulting in weight loss, although increased appetite and weight gain occasionally occur. Family and friends may notice agitation or lethargy. Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness, and a more noticeable slowing of movements.Depressed children may often display an irritable rather than a depressed mood; most lose interest in school and show a steep decline in academic performance. Diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness." Elderly people may not present with classical depressive symptoms. Diagnosis and treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have other concurrent diseases. Cause The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression. The diathesis–stress model specifies that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. The preexisting vulnerability can be either genetic, implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood. American psychiatrist Aaron Beck suggested that a triad of automatic and spontaneous negative thoughts about the self, the world or environment, and the future may lead to other depressive signs and symptoms.Adverse childhood experiences (incorporating childhood abuse, neglect and family dysfunction) markedly increase the risk of major depression, especially if more than one type. Childhood trauma also correlates with severity of depression, poor responsiveness to treatment and length of illness. Some are more susceptible than others to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility. Genetics Family and twin studies find that nearly 40% of individual differences in risk for major depressive disorder can be explained by genetic factors. Like most psychiatric disorders, major depressive disorder is likely influenced by many individual genetic changes. In 2018, a genome-wide association study discovered 44 genetic variants linked to risk for major depression; a 2019 study found 102 variants in the genome linked to depression. Research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings. There are also other efforts to examine interactions between life stress and polygenic risk for depression. Other health problems Depression can also arise after a chronic or terminal medical condition, such as HIV/AIDS or asthma, and may be labeled "secondary depression." It is unknown whether the underlying diseases induce depression through effect on quality of life, or through shared etiologies (such as degeneration of the basal ganglia in Parkinsons disease or immune dysregulation in asthma). Depression may also be iatrogenic (the result of healthcare), such as drug-induced depression. Therapies associated with depression include interferons, beta-blockers, isotretinoin, contraceptives, cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, and hormonal agents such as gonadotropin-releasing hormone agonist. Substance use in early age is associated with increased risk of developing depression later in life. Depression occurring after giving birth is called postpartum depression and is thought to be the result of hormonal changes associated with pregnancy. Seasonal affective disorder, a type of depression associated with seasonal changes in sunlight, is thought to be triggered by decreased sunlight. Vitamin B2, B6 and B12 deficiency may cause depression in females. Pathophysiology The pathophysiology of depression is not completely understood, but current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA-axis dysfunction and structural or functional abnormalities of emotional circuits. Derived from the effectiveness of monoaminergic drugs in treating depression, the monoamine theory posits that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. First, acute depletion of tryptophan—a necessary precursor of serotonin and a monoamine—can cause depression in those in remission or relatives of people who are depressed, suggesting that decreased serotonergic neurotransmission is important in depression. Second, the correlation between depression risk and polymorphisms in the 5-HTTLPR gene, which codes for serotonin receptors, suggests a link. Third, decreased size of the locus coeruleus, decreased activity of tyrosine hydroxylase, increased density of alpha-2 adrenergic receptor, and evidence from rat models suggest decreased adrenergic neurotransmission in depression. Furthermore, decreased levels of homovanillic acid, altered response to dextroamphetamine, responses of depressive symptoms to dopamine receptor agonists, decreased dopamine receptor D1 binding in the striatum, and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression. Lastly, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression. However, the monoamine theory is inconsistent with observations that serotonin depletion does not cause depression in healthy persons, that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway. One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitization of self-inhibition in raphe nuclei by the increased serotonin mediated by antidepressants. However, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. Further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls, the finding of increased jugular 5-HIAA in people who are depressed that normalized with selective serotonin reuptake inhibitor (SSRI) treatment, and the preference for carbohydrates in people who are depressed. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. A 2022 review found no consistent evidence supporting the serotonin hypothesis, linking serotonin levels and depression.Immune system abnormalities have been observed, including increased levels of cytokines involved in generating sickness behavior (which shares overlap with depression). The effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors in treating depression, and normalization of cytokine levels after successful treatment further suggest immune system abnormalities in depression.HPA-axis abnormalities have been suggested in depression given the association of CRHR1 with depression and the increased frequency of dexamethasone test non-suppression in people who are depressed. However, this abnormality is not adequate as a diagnosis tool, because its sensitivity is only 44%. These stress-related abnormalities are thought to be the cause of hippocampal volume reductions seen in people who are depressed. Furthermore, a meta-analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors. Further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.Theories unifying neuroimaging findings have been proposed. The first model proposed is the limbic-cortical model, which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing. Another model, the cortico-striatal model, suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures result in depression. Another model proposes hyperactivity of salience structures in identifying negative stimuli, and hypoactivity of cortical regulatory structures resulting in a negative emotional bias and depression, consistent with emotional bias studies. Diagnosis Clinical assessment A diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist, who records the persons current circumstances, biographical history, current symptoms, family history, and alcohol and drug use. The assessment also includes a mental state examination, which is an assessment of the persons current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans. Specialist mental health services are rare in rural areas, and thus diagnosis and management is left largely to primary-care clinicians. This issue is even more marked in developing countries. Rating scales are not used to diagnose depression, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose; these include the Hamilton Rating Scale for Depression, the Beck Depression Inventory or the Suicide Behaviors Questionnaire-Revised.Primary-care physicians have more difficulty with underrecognition and undertreatment of depression compared to psychiatrists. These cases may be missed because for some people with depression, physical symptoms often accompany depression. In addition, there may also be barriers related to the person, provider, and/or the medical system. Non-psychiatrist physicians have been shown to miss about two-thirds of cases, although there is some evidence of improvement in the number of missed cases.A doctor generally performs a medical examination and selected investigations to rule out other causes of depressive symptoms. These include blood tests measuring TSH and thyroxine to exclude hypothyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and a full blood count including ESR to rule out a systemic infection or chronic disease. Adverse affective reactions to medications or alcohol misuse may be ruled out, as well. Testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men. Vitamin D levels might be evaluated, as low levels of vitamin D have been associated with greater risk for depression. Subjective cognitive complaints appear in older depressed people, but they can also be indicative of the onset of a dementing disorder, such as Alzheimers disease. Cognitive testing and brain imaging can help distinguish depression from dementia. A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms. No biological tests confirm major depression. In general, investigations are not repeated for a subsequent episode unless there is a medical indication. DSM and ICD criteria The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders (DSM) and the World Health Organizations International Statistical Classification of Diseases and Related Health Problems (ICD). The latter system is typically used in European countries, while the former is used in the US and many other non-European nations, and the authors of both have worked towards conforming one with the other. Both DSM and ICD mark out typical (main) depressive symptoms. The most recent edition of the DSM is the Fifth Edition, Text Revision (DSM-5-TR), and the most recent edition of the ICD is the Eleventh Edition (ICD-11).Under mood disorders, ICD-11 classifies major depressive disorder as either single episode depressive disorder (where there is no history of depressive episodes, or of mania) or recurrent depressive disorder (where there is a history of prior episodes, with no history of mania). ICD-11 symptoms, present nearly every day for at least two weeks, are a depressed mood or anhedonia, accompanied by other symptoms such as "difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue." These symptoms must affect work, social, or domestic activities. The ICD-11 system allows further specifiers for the current depressive episode: the severity (mild, moderate, severe, unspecified); the presence of psychotic symptoms (with or without psychotic symptoms); and the degree of remission if relevant (currently in partial remission, currently in full remission). These two disorders are classified as "Depressive disorders", in the category of "Mood disorders".According to DSM-5, there are two main depressive symptoms: a depressed mood, and loss of interest/pleasure in activities (anhedonia). These symptoms, as well as five out of the nine more specific symptoms listed, must frequently occur for more than two weeks (to the extent in which it impairs functioning) for the diagnosis. Major depressive disorder is classified as a mood disorder in DSM-5. The diagnosis hinges on the presence of single or recurrent major depressive episodes. Further qualifiers are used to classify both the episode itself and the course of the disorder. The category Unspecified Depressive Disorder is diagnosed if the depressive episodes manifestation does not meet the criteria for a major depressive episode. Major depressive episode A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks. Episodes may be isolated or recurrent and are categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). An episode with psychotic features—commonly referred to as psychotic depression—is automatically rated as severe. If the person has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or "pole".Bereavement is not an exclusion criterion in DSM-5, and it is up to the clinician to distinguish between normal reactions to a loss and MDD. Excluded are a range of related diagnoses, including dysthymia, which involves a chronic but milder mood disturbance; recurrent brief depression, consisting of briefer depressive episodes; minor depressive disorder, whereby only some symptoms of major depression are present; and adjustment disorder with depressed mood, which denotes low mood resulting from a psychological response to an identifiable event or stressor. Subtypes The DSM-5 recognizes six further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features: "Melancholic depression" is characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt. "Atypical depression" is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (comfort eating), excessive sleep or sleepiness (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant long-term social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. "Catatonic depression" is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporous, and either remains immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms also occur in schizophrenia or in manic episodes, or may be caused by neuroleptic malignant syndrome. "Depression with anxious distress" was added into the DSM-5 as a means to emphasize the common co-occurrence between depression or mania and anxiety, as well as the risk of suicide of depressed individuals with anxiety. Specifying in such a way can also help with the prognosis of those diagnosed with a depressive or bipolar disorder. "Depression with peri-partum onset" refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth or while a woman is pregnant. DSM-IV-TR used the classification "postpartum depression," but this was changed to not exclude cases of depressed woman during pregnancy. Depression with peripartum onset has an incidence rate of 3–6% among new mothers. The DSM-V mandates that to qualify as depression with peripartum onset, onset occurs during pregnancy or within one month of delivery. "Seasonal affective disorder" (SAD) is a form of depression in which depressive episodes come on in the autumn or winter, and resolve in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times, over a two-year period or longer. Differential diagnoses To confirm major depressive disorder as the most likely diagnosis, other potential diagnoses must be considered, including dysthymia, adjustment disorder with depressed mood, or bipolar disorder. Dysthymia is a chronic, milder mood disturbance in which a person reports a low mood almost daily over a span of at least two years. The symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to secondary episodes of major depression (sometimes referred to as double depression). Adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioral symptoms are significant but do not meet the criteria for a major depressive episode.Other disorders need to be ruled out before diagnosing major depressive disorder. They include depressions due to physical illness, medications, and substance use disorders. Depression due to physical illness is diagnosed as a mood disorder due to a general medical condition. This condition is determined based on history, laboratory findings, or physical examination. When the depression is caused by a medication, non-medical use of a psychoactive substance, or exposure to a toxin, it is then diagnosed as a specific mood disorder (previously called substance-induced mood disorder). Screening and prevention Preventive efforts may result in decreases in rates of the condition of between 22 and 38%. Since 2016, the United States Preventive Services Task Force (USPSTF) has recommended screening for depression among those over the age 12; though a 2005 Cochrane review found that the routine use of screening questionnaires has little effect on detection or treatment. Screening the general population is not recommended by authorities in the UK or Canada.Behavioral interventions, such as interpersonal therapy and cognitive-behavioral therapy, are effective at preventing new onset depression. Because such interventions appear to be most effective when delivered to individuals or small groups, it has been suggested that they may be able to reach their large target audience most efficiently through the Internet.The Netherlands mental health care system provides preventive interventions, such as the "Coping with Depression" course (CWD) for people with sub-threshold depression. The course is claimed to be the most successful of psychoeducational interventions for the treatment and prevention of depression (both for its adaptability to various populations and its results), with a risk reduction of 38% in major depression and an efficacy as a treatment comparing favorably to other psychotherapies. Management The most common and effective treatments for depression are psychotherapy, medication, and electroconvulsive therapy (ECT); a combination of treatments is the most effective approach when depression is resistant to treatment. American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors including severity of symptoms, co-existing disorders, prior treatment experience, and personal preference. Options may include pharmacotherapy, psychotherapy, exercise, ECT, transcranial magnetic stimulation (TMS) or light therapy. Antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all people with severe depression unless ECT is planned. There is evidence that collaborative care by a team of health care practitioners produces better results than routine single-practitioner care.Psychotherapy is the treatment of choice (over medication) for people under 18, and cognitive behavioral therapy (CBT), third wave CBT and interpersonal therapy may help prevent depression. The UK National Institute for Health and Care Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression because the risk-benefit ratio is poor. The guidelines recommend that antidepressants treatment in combination with psychosocial interventions should be considered for: People with a history of moderate or severe depression Those with mild depression that has been present for a long period As a second line treatment for mild depression that persists after other interventions As a first line treatment for moderate or severe depression.The guidelines further note that antidepressant treatment should be continued for at least six months to reduce the risk of relapse, and that SSRIs are better tolerated than tricyclic antidepressants.Treatment options are more limited in developing countries, where access to mental health staff, medication, and psychotherapy is often difficult. Development of mental health services is minimal in many countries; depression is viewed as a phenomenon of the developed world despite evidence to the contrary, and not as an inherently life-threatening condition. There is insufficient evidence to determine the effectiveness of psychological versus medical therapy in children. Lifestyle Physical exercise has been found to be effective for major depression, and may be recommended to people who are willing, motivated, and healthy enough to participate in an exercise program as treatment. It is equivalent to the use of medications or psychological therapies in most people. In older people it does appear to decrease depression. Sleep and diet may also play a role in depression, and interventions in these areas may be an effective add-on to conventional methods. In observational studies, smoking cessation has benefits in depression as large as or larger than those of medications. Talking therapies Talking therapy (psychotherapy) can be delivered to individuals, groups, or families by mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, counselors, and psychiatric nurses. A 2012 review found psychotherapy to be better than no treatment but not other treatments. With more complex and chronic forms of depression, a combination of medication and psychotherapy may be used. There is moderate-quality evidence that psychological therapies are a useful addition to standard antidepressant treatment of treatment-resistant depression in the short term. Psychotherapy has been shown to be effective in older people. Successful psychotherapy appears to reduce the recurrence of depression even after it has been stopped or replaced by occasional booster sessions. The most-studied form of psychotherapy for depression is CBT, which teaches clients to challenge self-defeating, but enduring ways of thinking (cognitions) and change counter-productive behaviors. CBT can perform as well as antidepressants in people with major depression. CBT has the most research evidence for the treatment of depression in children and adolescents, and CBT and interpersonal psychotherapy (IPT) are preferred therapies for adolescent depression. In people under 18, according to the National Institute for Health and Clinical Excellence, medication should be offered only in conjunction with a psychological therapy, such as CBT, interpersonal therapy, or family therapy. Several variables predict success for cognitive behavioral therapy in adolescents: higher levels of rational thoughts, less hopelessness, fewer negative thoughts, and fewer cognitive distortions. CBT is particularly beneficial in preventing relapse. Cognitive behavioral therapy and occupational programs (including modification of work activities and assistance) have been shown to be effective in reducing sick days taken by workers with depression. Several variants of cognitive behavior therapy have been used in those with depression, the most notable being rational emotive behavior therapy, and mindfulness-based cognitive therapy. Mindfulness-based stress reduction programs may reduce depression symptoms. Mindfulness programs also appear to be a promising intervention in youth. Problem solving therapy, cognitive behavioral therapy, and interpersonal therapy are effective interventions in the elderly.Psychoanalysis is a school of thought, founded by Sigmund Freud, which emphasizes the resolution of unconscious mental conflicts. Psychoanalytic techniques are used by some practitioners to treat clients presenting with major depression. A more widely practiced therapy, called psychodynamic psychotherapy, is in the tradition of psychoanalysis but less intensive, meeting once or twice a week. It also tends to focus more on the persons immediate problems, and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials of Short Psychodynamic Supportive Psychotherapy, this modification was found to be as effective as medication for mild to moderate depression. Antidepressants Conflicting results have arisen from studies that look at the effectiveness of antidepressants in people with acute, mild to moderate depression. A review commissioned by the National Institute for Health and Care Excellence (UK) concluded that there is strong evidence that SSRIs, such as escitalopram, paroxetine, and sertraline, have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression. Similarly, a Cochrane systematic review of clinical trials of the generic tricyclic antidepressant amitriptyline concluded that there is strong evidence that its efficacy is superior to placebo. Antidepressants work less well for the elderly than for younger individuals with depression.To find the most effective antidepressant medication with minimal side-effects, the dosages can be adjusted, and if necessary, combinations of different classes of antidepressants can be tried. Response rates to the first antidepressant administered range from 50 to 75%, and it can take at least six to eight weeks from the start of medication to improvement. Antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimize the chance of recurrence, and even up to one year of continuation is recommended. People with chronic depression may need to take medication indefinitely to avoid relapse.SSRIs are the primary medications prescribed, owing to their relatively mild side-effects, and because they are less toxic in overdose than other antidepressants. People who do not respond to one SSRI can be switched to another antidepressant, and this results in improvement in almost 50% of cases. Another option is to switch to the atypical antidepressant bupropion. Venlafaxine, an antidepressant with a different mechanism of action, may be modestly more effective than SSRIs. However, venlafaxine is not

Major depressive disorder

recommended in the UK as a first-line treatment because of evidence suggesting its risks may outweigh benefits, and it is specifically discouraged in children and adolescents as it increases the risk of suicidal thoughts or attempts.For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy) but more research is needed to be certain. Sertraline, escitalopram, duloxetine might also help in reducing symptoms. Some antidepressants have not been shown to be effective. Medications are not recommended in children with mild disease.There is also insufficient evidence to determine effectiveness in those with depression complicated by dementia. Any antidepressant can cause low blood sodium levels; nevertheless, it has been reported more often with SSRIs. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating atypical antidepressant mirtazapine can be used in such cases.Irreversible monoamine oxidase inhibitors, an older class of antidepressants, have been plagued by potentially life-threatening dietary and drug interactions. They are still used only rarely, although newer and better-tolerated agents of this class have been developed. The safety profile is different with reversible monoamine oxidase inhibitors, such as moclobemide, where the risk of serious dietary interactions is negligible and dietary restrictions are less strict.It is unclear whether antidepressants affect a persons risk of suicide. For children, adolescents, and probably young adults between 18 and 24 years old, there is a higher risk of both suicidal ideations and suicidal behavior in those treated with SSRIs. For adults, it is unclear whether SSRIs affect the risk of suicidality. One review found no connection; another an increased risk; and a third no risk in those 25–65 years old and a decreased risk in those more than 65. A black box warning was introduced in the United States in 2007 on SSRIs and other antidepressant medications due to the increased risk of suicide in people younger than 24 years old. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health. Other medications and supplements The combined use of antidepressants plus benzodiazepines demonstrates improved effectiveness when compared to antidepressants alone, but these effects may not endure. The addition of a benzodiazepine is balanced against possible harms and other alternative treatment strategies when antidepressant mono-therapy is considered inadequate.Ketamine may have a rapid antidepressant effect lasting less than two weeks; there is limited evidence of any effect after that, common acute side effects, and longer-term studies of safety and adverse effects are needed. A nasal spray form of esketamine was approved by the FDA in March 2019 for use in treatment-resistant depression when combined with an oral antidepressant; risk of substance use disorder and concerns about its safety, serious adverse effects, tolerability, effect on suicidality, lack of information about dosage, whether the studies on it adequately represent broad populations, and escalating use of the product have been raised by an international panel of experts.There is insufficient high quality evidence to suggest omega-3 fatty acids are effective in depression. There is limited evidence that vitamin D supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin D-deficient. Lithium appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression to nearly the same levels as the general population. There is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed. Low-dose thyroid hormone may be added to existing antidepressants to treat persistent depression symptoms in people who have tried multiple courses of medication. Limited evidence suggests stimulants, such as amphetamine and modafinil, may be effective in the short term, or as adjuvant therapy. Also, it is suggested that folate supplements may have a role in depression management. There is tentative evidence for benefit from testosterone in males. Electroconvulsive therapy Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in a person with depression to provide relief from psychiatric illnesses.: 1880  ECT is used with informed consent as a last line of intervention for major depressive disorder. A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond relapse within twelve months. Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anesthesia.: 259  Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.A usual course of ECT involves multiple administrations, typically given two or three times per week, until the person no longer has symptoms. ECT is administered under anesthesia with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some people receive maintenance ECT.ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe. Other Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a noninvasive method used to stimulate small regions of the brain. TMS was approved by the FDA for treatment-resistant major depressive disorder (trMDD) in 2008 and as of 2014 evidence supports that it is probably effective. The American Psychiatric Association, the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed TMS for trMDD. Transcranial direct current stimulation (tDCS) is another noninvasive method used to stimulate small regions of the brain with a weak electric current. Several meta-analyses have concluded that active tDCS was useful for treating depression.There is a small amount of evidence that sleep deprivation may improve depressive symptoms in some individuals, with the effects usually showing up within a day. This effect is usually temporary. Besides sleepiness, this method can cause a side effect of mania or hypomania. There is insufficient evidence for Reiki and dance movement therapy in depression. Cannabis is specifically not recommended as a treatment. Prognosis Studies have shown that 80% of those with a first major depressive episode will have at least one more during their life, with a lifetime average of four episodes. Other general population studies indicate that around half those who have an episode recover (whether treated or not) and remain well, while the other half will have at least one more, and around 15% of those experience chronic recurrence. Studies recruiting from selective inpatient sources suggest lower recovery and higher chronicity, while studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. Around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence. Cases when outcome is poor are associated with inappropriate treatment, severe initial symptoms including psychosis, early age of onset, previous episodes, incomplete recovery after one year of treatment, pre-existing severe mental or medical disorder, and family dysfunction.A high proportion of people who experience full symptomatic remission still have at least one not fully resolved symptom after treatment. Recurrence or chronicity is more likely if symptoms have not fully resolved with treatment. Current guidelines recommend continuing antidepressants for four to six months after remission to prevent relapse. Evidence from many randomized controlled trials indicates continuing antidepressant medications after recovery can reduce the chance of relapse by 70% (41% on placebo vs. 18% on antidepressant). The preventive effect probably lasts for at least the first 36 months of use.Major depressive episodes often resolve over time, whether or not they are treated. Outpatients on a waiting list show a 10–15% reduction in symptoms within a few months, with approximately 20% no longer meeting the full criteria for a depressive disorder. The median duration of an episode has been estimated to be 23 weeks, with the highest rate of recovery in the first three months. According to a 2013 review, 23% of untreated adults with mild to moderate depression will remit within 3 months, 32% within 6 months and 53% within 12 months. Ability to work Depression may affect peoples ability to work. The combination of usual clinical care and support with return to work (like working less hours or changing tasks) probably reduces sick leave by 15%, and leads to fewer depressive symptoms and improved work capacity, reducing sick leave by an annual average of 25 days per year. Helping depressed people return to work without a connection to clinical care has not been shown to have an effect on sick leave days. Additional psychological interventions (such as online cognitive behavioral therapy) lead to fewer sick days compared to standard management only. Streamlining care or adding specific providers for depression care may help to reduce sick leave. Life expectancy and the risk of suicide Depressed individuals have a shorter life expectancy than those without depression, in part because people who are depressed are at risk of dying of suicide. About 50% of people who die of suicide have a mood disorder such as major depression, and the risk is especially high if a person has a marked sense of hopelessness or has both depression and borderline personality disorder. About 2–8% of adults with major depression die by suicide. In the US, the lifetime risk of suicide associated with a diagnosis of major depression is estimated at 7% for men and 1% for women, even though suicide attempts are more frequent in women.Depressed people have a higher rate of dying from other causes. There is a 1.5- to 2-fold increased risk of cardiovascular disease, independent of other known risk factors, and is itself linked directly or indirectly to risk factors such as smoking and obesity. People with major depression are less likely to follow medical recommendations for treating and preventing cardiovascular disorders, further increasing their risk of medical complications. Cardiologists may not recognize underlying depression that complicates a cardiovascular problem under their care. Epidemiology Major depressive disorder affected approximately 163 million people in 2017 (2% of the global population). The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. In most countries the number of people who have depression during their lives falls within an 8–18% range.In the United States, 8.4% of adults (21 million individuals) have at least one episode within a year-long period; the probability of having a major depressive episode is higher for females than males (10.5% to 6.2%), and highest for those aged 18 to 25 (17%). Among adolescents between the ages of 12 and 17, 17% of the U.S. population (4.1 million individuals) had a major depressive episode in 2020 (females 25.2%, males 9.2%). Among individuals reporting two or more races, the US prevalence is highest.Major depression is about twice as common in women as in men, although it is unclear why this is so, and whether factors unaccounted for are contributing to this. The relative increase in occurrence is related to pubertal development rather than chronological age, reaches adult ratios between the ages of 15 and 18, and appears associated with psychosocial more than hormonal factors. In 2019, major depressive disorder was identified (using either the DSM-IV-TR or ICD-10) in the Global Burden of Disease Study as the fifth most common cause of years lived with disability and the 18th most common for disability-adjusted life years.People are most likely to develop their first depressive episode between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60. The risk of major depression is increased with neurological conditions such as stroke, Parkinsons disease, or multiple sclerosis, and during the first year after childbirth. It is also more common after cardiovascular illnesses, and is related more to those with a poor cardiac disease outcome than to a better one. Depressive disorders are more common in urban populations than in rural ones and the prevalence is increased in groups with poorer socioeconomic factors, e.g., homelessness. Depression is common among those over 65 years of age and increases in frequency beyond this age. The risk of depression increases in relation to the frailty of the individual. Depression is one of the most important factors which negatively impact quality of life in adults, as well as the elderly. Both symptoms and treatment among the elderly differ from those of the rest of the population.Major depression was the leading cause of disease burden in North America and other high-income countries, and the fourth-leading cause worldwide as of 2006. In the year 2030, it is predicted to be the second-leading cause of disease burden worldwide after HIV, according to the WHO. Delay or failure in seeking treatment after relapse and the failure of health professionals to provide treatment are two barriers to reducing disability. Comorbidity Major depression frequently co-occurs with other psychiatric problems. The 1990–92 National Comorbidity Survey (US) reported that half of those with major depression also have lifetime anxiety and its associated disorders, such as generalized anxiety disorder. Anxiety symptoms can have a major impact on the course of a depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicidal behavior. Depressed people have increased rates of alcohol and substance use, particularly dependence, and around a third of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) develop comorbid depression. Post-traumatic stress disorder and depression often co-occur. Depression may also coexist with ADHD, complicating the diagnosis and treatment of both. Depression is also frequently comorbid with alcohol use disorder and personality disorders. Depression can also be exacerbated during particular months (usually winter) in those with seasonal affective disorder. While overuse of digital media has been associated with depressive symptoms, using digital media may also improve mood in some situations.Depression and pain often co-occur. One or more pain symptoms are present in 65% of people who have depression, and anywhere from 5 to 85% of people who are experiencing pain will also have depression, depending on the setting—a lower prevalence in general practice, and higher in specialty clinics. Depression is often underrecognized, and therefore undertreated, in patients presenting with pain. Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinsons disease, and chronic obstructive pulmonary disease. History The Ancient Greek physician Hippocrates described a syndrome of melancholia (μελαγχολία, melankholía) as a distinct disease with particular mental and physical symptoms; he characterized all "fears and despondencies, if they last a long time" as being symptomatic of the ailment. It was a similar but far broader concept than todays depression; prominence was given to a clustering of the symptoms of sadness, dejection, and despondency, and often fear, anger, delusions and obsessions were included. The term depression itself was derived from the Latin verb deprimere, meaning "to press down". From the 14th century, "to depress" meant to subjugate or to bring down in spirits. It was used in 1665 in English author Richard Bakers Chronicle to refer to someone having "a great depression of spirit", and by English author Samuel Johnson in a similar sense in 1753. The term also came into use in physiology and economics. An early usage referring to a psychiatric symptom was by French psychiatrist Louis Delasiauve in 1856, and by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function. Since Aristotle, melancholia had been associated with men of learning and intellectual brilliance, a hazard of contemplation and creativity. The newer concept abandoned these associations and through the 19th century, became more associated with women.Although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and was a synonym by the end of the century; German psychiatrist Emil Kraepelin may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states. Freud likened the state of melancholia to mourning in his 1917 paper Mourning and Melancholia. He theorized that objective loss, such as the loss of a valued relationship through death or a romantic break-up, results in subjective loss as well; the depressed individual has identified with the object of affection through an unconscious, narcissistic process called the libidinal cathexis of the ego. Such loss results in severe melancholic symptoms more profound than mourning; not only is the outside world viewed negatively but the ego itself is compromised. The persons decline of self-perception is revealed in his belief of his own blame, inferiority, and unworthiness. He also emphasized early life experiences as a predisposing factor. Adolf Meyer put forward a mixed social and biological framework emphasizing reactions in the context of an individuals life, and argued that the term depression should be used instead of melancholia. The first version of the DSM (DSM-I, 1952) contained depressive reaction and the DSM-II (1968) depressive neurosis, defined as an excessive reaction to internal conflict or an identifiable event, and also included a depressive type of manic-depressive psychosis within Major affective disorders.The term unipolar (along with the related term bipolar) was coined by the neurologist and psychiatrist Karl Kleist, and subsequently used by his disciples Edda Neele and Karl Leonhard.The term Major depressive disorder was introduced by a group of US clinicians in the mid-1970s as part of proposals for diagnostic criteria based on patterns of symptoms (called the "Research Diagnostic Criteria", building on earlier Feighner Criteria), and was incorporated into the DSM-III in 1980. The American Psychiatric Association added "major depressive disorder" to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), as a split of the previous depressive neurosis in the DSM-II, which also encompassed the conditions now known as dysthymia and adjustment disorder with depressed mood. To maintain consistency the ICD-10 used the same criteria, with only minor alterations, but using the DSM diagnostic threshold to mark a mild depressive episode, adding higher threshold categories for moderate and severe episodes. The ancient idea of melancholia still survives in the notion of a melancholic subtype. The new definitions of depression were widely accepted, albeit with some conflicting findings and views. There have been some continued empirically based arguments for a return to the diagnosis of melancholia. There has been some criticism of the expansion of coverage of the diagnosis, related to the development and promotion of antidepressants and the biological model since the late 1950s. Society and culture Terminology The term "depression" is used in a number of different ways. It is often used to mean this syndrome but may refer to other mood disorders or simply to a low mood. Peoples conceptualizations of depression vary widely, both within and among cultures. "Because of the lack of scientific certainty," one commentator has observed, "the debate over depression turns on questions of language. What we call it—disease, disorder, state of mind—affects how we view, diagnose, and treat it." There are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or an indicator of something else, such as the need to address social or moral problems, the result of biological imbalances, or a reflection of individual differences in the understanding of distress that may reinforce feelings of powerlessness, and emotional struggle. Stigma Historical figures were often reluctant to discuss or seek treatment for depression due to social stigma about the condition, or due to ignorance of diagnosis or treatments. Nevertheless, analysis or interpretation of letters, journals, artwork, writings, or statements of family and friends of some historical personalities has led to the presumption that they may have had some form of depression. People who may have had depression include English author Mary Shelley, American-British writer Henry James, and American president Abraham Lincoln. Some well-known contemporary people with possible depression include Canadian songwriter Leonard Cohen and American playwright and novelist Tennessee Williams. Some pioneering psychologists, such as Americans William James and John B. Watson, dealt with their own depression. There has been a continuing discussion of whether neurological disorders and mood disorders may be linked to creativity, a discussion that goes back to Aristotelian times. British literature gives many examples of reflections on depression. English philosopher John Stuart Mill experienced a several-months-long period of what he called "a dull state of nerves", when one is "unsusceptible to enjoyment or pleasurable excitement; one of those moods when what is pleasure at other times, becomes insipid or indifferent". He quoted English poet Samuel Taylor Coleridges "Dejection" as a perfect description of his case: "A grief without a pang, void, dark and drear, / A drowsy, stifled, unimpassioned grief, / Which finds no natural outlet or relief / In word, or sigh, or tear." English writer Samuel Johnson used the term "the black dog" in the 1780s to describe his own depression, and it was subsequently popularized by British Prime Minister Sir Winston Churchill, who also had the disorder. Johann Wolfgang von Goethe in his Faust, Part I, published in 1808, has Mephistopheles assume the form of a black dog, specifically a poodle. Social stigma of major depression is widespread, and contact with mental health services reduces this only slightly. Public opinions on treatment differ markedly to those of health professionals; alternative treatments are held to be more helpful than pharmacological ones, which are viewed poorly. In the UK, the Royal College of Psychiatrists and the Royal College of General Practitioners conducted a joint Five-year Defeat Depression campaign to educate and reduce stigma from 1992 to 1996; a MORI study conducted afterwards showed a small positive change in public attitudes to depression and treatment. References === Cited works ===

MERRF syndrome

MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the diseases name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age. Symptoms and signs An individual displaying MERRFs syndrome will manifest not only a single symptom, but patients regularly display more than one affected body part at a time. It has been observed that patients with MERRF syndrome will primarily display myoclonus as a first symptom. There may also be seizures, cerebellar ataxia and myopathy. Secondary features can include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, multiple lipomata, and/or cardiomyopathy with Wolff Parkinson-White syndrome. Most patients will not exhibit all of these symptoms, but more than one of these symptoms will be present in a patient who has been diagnosed with MERRF disease. Mitochondrial disorders, including MERRF, may present at any age. Due to the multiple symptoms presented by the individual, the severity of the syndrome is very difficult to evaluate. Causes The cause of MERRF disorder is due to mutations in the mitochondrial genome. This means that it is a pathological variant in mtDNA (mitochondrial DNA) and is transmitted by maternal inheritance. Four point mutations in the genome can be identified that are associated with MERRF: m.A8344G, m.T8356C, m.G8361A, and m.G8363A. The point mutation m.A8344G is most commonly associated with MERRF, in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama stated that 80% of the patients with MERRF disease exhibited this point mutation. This point mutation disrupts the mitochondrial gene for tRNA-Lys. This disrupts the synthesis of proteins. The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.Many genes are involved. These genes include: MT-TK MT-TL1 MT-TH MT-TS1 MT-TS2 MT-TFIt involves the following characteristics: progressive myoclonic epilepsy "Ragged Red Fibers" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain.There is currently no cure for MERRF. Mechanism The mechanism by which MERRFs syndrome occur is not yet well understood. The human mitochondrial tRNA mutations are associated with a variety of diseases including mitochondrial myopathies. However, it is understood that defects in the mitochondrial DNA (mtDNA) have been associated with these diseases, and studies have been able to assign biochemical defects. One of these defects has to do with the decreased energy available for cell processes. As muscles are stained with Gömöri trichrome, characteristic ragged red fibers are visible under the microscope. This appearance is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber. These may extend throughout the muscle fiber as the disease severity increases. The mitochondrial aggregates cause the contour of the muscle fiber to become irregular, leading to the "ragged" appearance. Diagnosis The diagnosis varies from individual to individual. Each is evaluated and diagnosed according to age, clinical phenotype, and pressed inheritance pattern. If the individual has been experiencing myoclonus, the doctor will run a series of genetic studies to determine if it is a mitochondrial disorder.The molecular genetic studies are run to identify the reason of for the mutations underlying the mitochondrial dysfunction. This approach will avoid the need for a muscle biopsy or an exhaustive metabolic evaluation. After sequencing the mitochondrial genomes, four points mutations in the genome can be identified which are associated with MERRF: A8344G, T8356C, G8361A, and G8363A. The point mutation A8344G is mostly associated with MERRF, in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama stated that 80% of the patients with MERRF disease exhibited this point mutation. The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.If a patient does not exhibit mitochondrial DNA mutations, there are other ways that they can be diagnosed with MERRF. They can go through computed tomography (CT) or magnetic resonance imaging (MRI).The classification for the severity of MERRF syndrome is difficult to distinguish since most individuals will exhibit multi-symptoms. This is often necessary for children with complex neurologic or multi-system involvement, as described below. History and physical examination of the patient A detailed family history should be obtained from at least three generations, particularly if there have been any neonatal and childhood deaths. A family history may also indicate if any family members exhibit features of the multi-system disease, specifically if there has been maternal inheritance. This would show transmission of the disease only to females, or if there is a family member who experienced a multi-system involvement such as: brain condition that a family member has been record to have such as seizures, dystonia, ataxia, or stroke-like episodes. There may also be optic atrophy, skeletal muscle with a history of myalgia, weakness, or ptosis. Family history may also include neuropathy and dysautonomia, or heart conditions such as cardiomyopathy. The patients history might also exhibit kidney problems, such as proximal nephron dysfunction. There may also be endocrine conditions, such as diabetes or hypoparathyroidism. The patient might have also had a gastrointestinal condition which could have been due to liver disease, as well as episodes of nausea or vomiting. Multiple lipomas in the skin, sideroblastic anemia and pancytopenia in the metabolic system, or short stature might all be examples of patients with possible symptoms of MERRF disease. Treatment Like many mitochondrial diseases, there is no cure for MERRF, no matter the means for diagnosis of the disease. The treatment is primarily symptomatic. High doses of coenzyme Q10, B complex vitamins, and L-Carnitine are used for the altered metabolic processing that results in the disease. There is very little success with these treatments as therapies in hopes of improving mitochondrial function. The treatment only alleviates symptoms, and these do not prevent the disease from progressing. Patients with concomitant disease, such as diabetes, deafness, or cardiac disease, are treated in combination to manage symptoms. Research The Journal of Child Neurology published a paper that discusses possible new methods to test for MERRF and other mitochondrial diseases through a simple swabbing technique. This is a less invasive technique which allows for an analysis of buccal mitochondrial DNA, and showed significant amounts of the common 5 kb and 7.4 kb mitochondrial DNA deletions, which are also detectable in blood. This study suggests that a buccal swab approach can be used to informatively examine mitochondrial dysfunction in children with seizures and may be applicable to screening mitochondrial disease with other clinical presentations.Proceedings of the National Academy of Science of the United States of America published an article investigating the human mitochondrial tRNA (hmt-tRNA) mutations which are associated with mitochondrial myopathies. Since the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. All pathogenic mutants displayed pleiotropic phenotypes, with the exception of the G34A anticodon mutation, which solely affected aminoacylation. See also Epilepsy Mitochondrial disease Myoclonus Ragged red fibers References External links MERRF+Syndrome at the US National Library of Medicine Medical Subject Headings (MeSH) merrf at NIH/UW GeneTests

Acute pericarditis

Acute pericarditis is a type of pericarditis (inflammation of the sac surrounding the heart, the pericardium) usually lasting less than 6 weeks. It is the most common condition affecting the pericardium. Signs and symptoms Chest pain is one of the common symptoms of acute pericarditis. It is usually of sudden onset, occurring in the anterior chest and often has a sharp quality that worsens with breathing in or coughing, due to inflammation of the pleural surface at the same time. The pain may be reduced with sitting up and leaning forward while worsened with lying down, and also may radiate to the back, to one or both trapezius ridges. However, the pain can also be dull and steady, resembling the chest pain in an acute myocardial infarction. As with any chest pain, other causes must also be ruled out, such as GERD, pulmonary embolism, muscular pain, etc. A pericardial friction rub is a very specific sign of acute pericarditis, meaning the presence of this sign invariably indicates presence of disease. However, absence of this sign does not rule out disease. This rub can be best heard by the diaphragm of the stethoscope at the left sternal border arising as a squeaky or scratching sound, resembling the sound of leather rubbing against each other. This sound should be distinguished from the sound of a murmur, which is similar but sounds more like a "swish" sound than a scratching sound. The pericardial rub is said to be generated from the friction generated by the two inflamed layers of the pericardium; however, even a large pericardial effusion does not necessarily present a rub. The rub is best heard during the maximal movement of the heart within the pericardial sac, namely, during atrial systole, ventricular systole, and the filling phase of early ventricular diastole. Fever may be present since this is an inflammatory process. Causes There are several causes of acute pericarditis. In developed nations, the cause of most (80–90%) cases of acute pericarditis is unknown but a viral cause is suspected in the majority of such cases. The other 10–20% of acute pericarditis cases have various causes including connective tissue diseases (e.g., systemic lupus erythematosus), cancer, or involve an inflammatory reaction of the pericardium following trauma to the heart such as after a heart attack such as Dresslers syndrome. Familial mediterranean fever and TNF receptor associated periodic syndrome are rare inherited autoimmune diseases capable of causing recurring episodes of acute pericarditis. Pathophysiology Clinical presentation of diseases of pericardium may vary between: Acute and recurrent pericarditis Pericardial effusion without major hemodynamic compromise Cardiac tamponade Constrictive pericarditis Effusive-constrictive pericarditis Diagnosis For acute pericarditis to formally be diagnosed, two or more of the following criteria must be present: chest pain consistent with a diagnosis of acute pericarditis (sharp chest pain worsened by breathing in or a cough), a pericardial friction rub, a pericardial effusion, and changes on electrocardiogram (ECG) consistent with acute pericarditis.A complete blood count may show an elevated white count and a serum C-reactive protein may be elevated. Acute pericarditis is associated with a modest increase in serum creatine kinase MB (CK-MB). and cardiac troponin I (cTnI), both of which are also markers for injury to the muscular layer of the heart. Therefore, it is imperative to also rule out acute myocardial infarction in the face of these biomarkers. The elevation of these substances may occur when inflammation of the hearts muscular layer in addition to acute pericarditis. Also, ST elevation on EKG (see below) is more common in those patients with a cTnI > 1.5 µg/L. Coronary angiography in those patients should indicate normal vascular perfusion. Troponin levels increase in 35-50% of people with pericarditis.Electrocardiogram (ECG) changes in acute pericarditis mainly indicates inflammation of the epicardium (the layer directly surrounding the heart), since the fibrous pericardium is electrically inert. For example, in uremia, there is no inflammation in the epicardium, only fibrin deposition, and therefore the EKG in uremic pericarditis will be normal. Typical EKG changes in acute pericarditis includes stage 1 -- diffuse, positive, ST elevations with reciprocal ST depression in aVR and V1. Elevation of PR segment in aVR and depression of PR in other leads especially left heart V5, V6 leads indicates atrial injury. stage 2 -- normalization of ST and PR deviations stage 3 -- diffuse T wave inversions (may not be present in all patients) stage 4 -- EKG becomes normal OR T waves may be indefinitely invertedThe two most common clinical conditions where ECG findings may mimic pericarditis are acute myocardial infarction (AMI) and generalized early repolarization. As opposed to pericarditis, AMI usually causes localized convex ST-elevation usually associated with reciprocal ST-depression which may also be frequently accompanied by Q-waves, T-wave inversions (while ST is still elevated unlike pericarditis), arrhythmias and conduction abnormalities. In AMI, PR-depressions are rarely present. Early repolarization usually occurs in young males (age <40 years) and ECG changes are characterized by terminal R-S slurring, temporal stability of ST-deviations and J-height/ T-amplitude ratio in V5 and V6 of <25% as opposed to pericarditis where terminal R-S slurring is very uncommon and J-height/ T-amplitude ratio is ≥ 25%. Very rarely, ECG changes in hypothermia may mimic pericarditis, however differentiation can be helpful by a detailed history and presence of an Osborne wave in hypothermia.Another important diagnostic electrocardiographic sign in acute pericarditis is the Spodick sign. It signifies to the PR-depressions in a usual (but not always) association with downsloping TP segment in patients with acute pericarditis and is present in up to 80% of the patients affected with acute pericarditis. The sign is often best visualized in lead II and lateral precordial leads. In addition, Spodicks sign may also serve as an important distinguishing electrocardiographic tool between the acute pericarditis and acute coronary syndrome. The presence of a classical Spodicks sign is often a giveaway to the diagnosis.Rarely, electrical alternans may be seen, depending on the size of the effusion.A chest x-ray is usually normal in acute pericarditis but can reveal the presence of an enlarged heart if a pericardial effusion is present and is greater than 200 mL in volume. Conversely, patients with unexplained new onset cardiomegaly should always be worked up for acute pericarditis.An echocardiogram is typically normal in acute pericarditis but can reveal pericardial effusion, the presence of which supports the diagnosis, although its absence does not exclude the diagnosis. Treatment Patients with uncomplicated acute pericarditis can generally be treated and followed up in an outpatient clinic. However, those with high risk factors for developing complications (see above) will need to be admitted to an inpatient service, most likely an ICU setting. High risk patients include the following: subacute onset high fever (> 100.4 F/38 C) and leukocytosis development of cardiac tamponade large pericardial effusion (echo-free space > 20 mm) resistant to NSAID treatment immunocompromised history of oral anticoagulation therapy acute trauma failure to respond to seven days of NSAID treatmentPericardiocentesis is a procedure whereby the fluid in a pericardial effusion is removed through a needle. It is performed under the following conditions: presence of moderate or severe cardiac tamponade diagnostic purpose for suspected purulent, tuberculosis, or neoplastic pericarditis persistent symptomatic pericardial effusionNSAIDs in viral or idiopathic pericarditis. In patients with underlying causes other than viral, the specific etiology should be treated. With idiopathic or viral pericarditis, NSAID is the mainstay treatment. Goal of therapy is to reduce pain and inflammation. The course of the disease may not be affected. The preferred NSAID is ibuprofen because of rare side effects, better effect on coronary flow, and larger dose range. Depending on severity, dosing is between 300 and 800 mg every 6–8 hours for days or weeks as needed. An alternative protocol is aspirin 800 mg every 6–8 hours. Dose tapering of NSAIDs may be needed. In pericarditis following acute myocardial infarction, NSAIDs other than aspirin should be avoided since they can impair scar formation. As with all NSAID use, GI protection should be engaged. Failure to respond to NSAIDs within one week (indicated by persistence of fever, worsening of condition, new pericardial effusion, or continuing chest pain) likely indicates that a cause other than viral or idiopathic is in process.Colchicine, which has been essential to treat recurrent pericarditis, has been supported for routine use in acute pericarditis by recent prospective studies. Colchicine can be given 0.6 mg twice a day (0.6 mg daily for patients <70 kg) for 3 months following an acute attack. It should be considered in all patients with acute pericarditis, preferably in combination with a short-course of NSAIDs. For patients with a first episode of acute idiopathic or viral pericarditis, they should be treated with an NSAID plus colchicine 1–2 mg on first day followed by 0.5 daily or twice daily for three months. It should be avoided or used with caution in patients with severe chronic kidney disease, hepatobiliary dysfunction, blood dyscrasias, and gastrointestinal motility disorders.Corticosteroids are usually used in those cases that are clearly refractory to NSAIDs and colchicine and a specific cause has not been found. Systemic corticosteroids are usually reserved for those with autoimmune disease. Prognosis One of the most feared complications of acute pericarditis is cardiac tamponade. Cardiac tamponade is accumulation of enough fluid in the pericardial space --- pericardial effusion --- to cause serious obstruction to the inflow of blood to the heart. Signs of cardiac tamponade include distended neck veins, muffled heart sounds when listening with a stethoscope, and low blood pressure (together known as Becks triad). This condition can be fatal if not immediately treated. Another longer term complication of pericarditis, if it recurs over a longer period of time (normally more than 3 months), is progression to constrictive pericarditis. Recent studies have shown this to be an uncommon complication. The definitive treatment for constrictive pericarditis is pericardial stripping, which is a surgical procedure where the entire pericardium is peeled away from the heart. References Further reading Chugh, S. N. (2014-05-14). Textbook of Clinical Electrocardiography. Jaypee Brothers Publishers. ISBN 9789350906088. == External links ==

Ulcerative colitis

Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.The cause of UC is unknown. Theories involve immune system dysfunction, genetics, changes in the normal gut bacteria, and environmental factors. Rates tend to be higher in the developed world with some proposing this to be the result of less exposure to intestinal infections, or to a Western diet and lifestyle. The removal of the appendix at an early age may be protective. Diagnosis is typically by colonoscopy with tissue biopsies. It is a type of inflammatory bowel disease (IBD) along with Crohns disease and microscopic colitis.Dietary changes, such as maintaining a high-calorie diet or lactose-free diet, may improve symptoms. Several medications are used to treat symptoms and bring about and maintain remission, including aminosalicylates such as mesalazine or sulfasalazine, steroids, immunosuppressants such as azathioprine, and biologic therapy. Removal of the colon by surgery may be necessary if the disease is severe, does not respond to treatment, or if complications such as colon cancer develop. Removal of the colon and rectum generally cures the condition.Together with Crohns disease, about 11.2 million people were affected as of 2015. Each year it newly occurs in 1 to 20 per 100,000 people, and 5 to 500 per 100,000 individuals are affected. The disease is more common in North America and Europe than other regions. Often it begins in people aged 15 to 30 years, or among those over 60. Males and females appear to be affected in equal proportions. It has also become more common since the 1950s. Together, ulcerative colitis and Crohns disease affect about a million people in the United States. With appropriate treatment the risk of death appears the same as that of the general population. The first description of ulcerative colitis occurred around the 1850s. Signs and symptoms Gastrointestinal People with ulcerative colitis usually present with diarrhea mixed with blood, of gradual onset that persists for an extended period of time (weeks). Additional symptoms may include fecal incontinence, increased frequency of bowel movements, mucus discharge, and nocturnal defecations. With proctitis (inflammation of the rectum), people with UC may experience urgency or rectal tenesmus, which is the urgent desire to evacuate the bowels but with the passage of little stool. Tenesmus may be misinterpreted as constipation, due to the urge to defecate despite small volume of stool passage. Bloody diarrhea and abdominal pain may be more prominent features in severe disease. The severity of abdominal pain with UC varies from mild discomfort to very painful bowel movements and abdominal cramping. High frequency of bowel movements, weight loss, nausea, fatigue, and fever are also common during disease flares. Chronic bleeding from the GI tract, chronic inflammation, and iron deficiency often leads to anemia, which can affect quality of life.The clinical presentation of ulcerative colitis depends on the extent of the disease process. Up to 15% of individuals may have severe disease upon initial onset of symptoms. A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease. Extent of involvement In contrast to Crohns disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to sigmoid colon, ascending colon, etc.). In contrast, inflammation with Crohns disease is often patchy, with so-called "skip lesions" (intermittent regions of inflamed bowel).The disease is classified by the extent of involvement, depending on how far the disease extends: proctitis (rectal inflammation), left sided colitis (inflammation extending to descending colon), and extensive colitis (inflammation proximal to the descending colon). Proctosigmoiditis describes inflammation of the rectum and sigmoid colon. Pancolitis describes involvement of the entire colon, extending from the rectum to the cecum. While usually associated with Crohns disease, ileitis (inflammation of the ileum) also occurs in UC. About 17% of individuals with UC have ileitis. Ileitis more commonly occurs in the setting of pancolitis (occurring in 20% of cases of pancolitis), and tends to correlate with the activity of colitis. This so-called "backwash ileitis" can occur in 10–20% of people with pancolitis and is believed to be of little clinical significance. Severity of disease In addition to the extent of involvement, UC is also characterized by severity of disease. Severity of disease is defined by symptoms, objective markers of inflammation (endoscopic findings, blood tests), disease course, and the impact of the disease on day-to-day life. Most patients are categorized through endoscopy and fecal calprotectin levels. Indicators of low risk for future complications in mild and moderate UC include the following parameters: exhibiting less than 6 stools daily and lack of fever/weight loss. Other indicators include lack of extraintestinal symptoms, none to little elevation in CRP, ESR, and calprotectin, and later age of diagnosis (over 40 years). Mild disease correlates with fewer than four stools daily; in addition, mild urgency and rectal bleeding may occur intermittently. Mild disease lacks systemic signs of toxicity (eg. fever, chills, weight changes) and exhibits normal levels of serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein).Moderate to severe disease correlates with more than six stools daily, frequent bloody stools and urgency. Moderate abdominal pain, low-grade fever, 38 to 39 °C (100 to 102 °F), and anemia may develop (75% of normal). Toxicity is present, as demonstrated by fever, tachycardia, anemia or an elevated ESR or CRP.Fulminant disease correlates with more than 10 bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation (expansion). People with fulminant UC may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. Toxic megacolon is defined by diameter of colon (>6 cm) or cecum (>9 cm) and represents a medical emergency, one often treated surgically. If the serous membrane is involved, a colonic perforation may ensue, which has a 50% mortality rate in patients afflicted with UC.Ulcerative colitis may improve and enter remission. Remission of disease is characterized by formed stools, the absence of bloody diarrhea, resolution of urgency, and normal levels of serum inflammatory markers. Extraintestinal manifestations and complications UC is characterized by immune dysregulation and systemic inflammation, which may result in symptoms and complications outside the colon. Commonly affected organs include: eyes, joints, skin, and liver. The frequency of such extraintestinal manifestations has been reported as between 6 and 47%.UC may affect the mouth. About 8% of individuals with UC develop oral manifestations. The two most common oral manifestations are aphthous stomatitis and angular cheilitis. Aphthous stomatitis is characterized by ulcers in the mouth, which are benign, noncontagious and often recurrent. Angular chelitis is characterized by redness at the corners of the mouth, which may include painful sores or breaks in the skin. Very rarely, benign pustules may occur in the mouth (pyostomatitis vegetans).UC may affect the eyes manifesting in scleritis, iritis, and conjunctivitis. Patients may be asymptomatic or experience redness, burning, or itching in eyes (CITE CMDP). Inflammation may occur in the interior portion of the eye, leading to uveitis and iritis. Uveitis can cause blurred vision and eye pain, especially when exposed to light (photophobia). Untreated, uveitis can lead to permanent vision loss. Inflammation may also involve the white part of the eye (sclera) or the overlying connective tissue (episclera), causing conditions called scleritis and episcleritis. Ulcerative colitis is most commonly associated with uveitis and episcleritis.UC may cause several joint manifestations, including a type of rheumatologic disease known as seronegative arthritis, which may affect few large joints (oligoarthritis), the vertebra (ankylosing spondylitis) or several small joints of the hands and feet (peripheral arthritis). Often the insertion site where muscle attaches to bone (entheses) becomes inflamed (enthesitis). Inflammation may affect the sacroiliac joint (sacroiliitis). It is estimated that round 50% of IBD patients suffer from migratory arthritis. Synovitis, or inflammation of the synovial fluid surrounding a joint, can occur for months and recur in later times but usually does not erode the joint. The symptoms of arthritis include joint pain, swelling, and effusion, and often leads to significant morbidity. The severity of joint symptoms often does not correspond with severity of IBD. Ulcerative colitis may affect the skin. The most common type of skin manifestation, erythema nodosum, presents in up to 3% of UC patients and almost 8% in patients afflicted with Crohns disease. It develops as raised, tender red nodules usually appearing on the outer areas of the arms or legs, especially in the anterior tibial area (shins). The nodules have diameters that measure approximately 1–5 cm. Erythema nodosum is due to inflammation of the underlying subcutaneous tissue (panniculitis), and biopsy will display focal panniculitis (although is often unnecessary in diagnosis). In contrast to joint-related manifestations, erythema nodosum often occurs alongside intestinal disease. Thus, treatment of UC can often lead to resolution of skin nodules.A lesser common skin complication associated with UC, pyoderma gangrenosum, is typically more severe. One study discovered this skin manifestation in only 0.75% pf patients. Pyoderma gangrenosum is characterized by painful lesions or nodules that become ulcers which progressively grow. It often starts as many small raised red spots (papules) or pus-filled lesions (pustules) that are usually detected on lower extremities. The inner layer of the skin, or dermis, slowly undergoes necrosis (process of dying) causing the ulcerations that are typical of pyoderma gangrenosum. The ulcers are often filled with sterile pus-like material, so biopsy often displays an abscess that is sterile. Whereas erythema nodosum tends to correlate with the activity of the ulcerative colitis and often improves with treatment of the colonic inflammation, pyoderma gangrenosum may occur independently of UC disease activity. In some cases, pyoderma gangrenosum may require injection with corticosteroids. Treatment may also involve inhibitors of tumor necrosis factor (TNF), a cytokine that promotes cell survival.Other associations determined between the skin and ulcerative colitis include a skin condition known as hidradenitis suppurativa (HS). This condition represents a chronic process in which follicles become occluded leading to recurring inflammation of nodules and abscesses and even tunnels in the skin that drain fluid.Ulcerative colitis may affect the blood and endocrine system. UC increases the risk of blood clots in both arteries and veins; painful swelling of the lower legs can be a sign of deep venous thrombosis, while difficulty breathing may be a result of pulmonary embolism (blood clots in the lungs). The risk of blood clots is about threefold higher in individuals with IBD. The risk of venous thromboembolism is high in ulcerative colitis due to hypercoagulability from inflammation, especially with active or extensive disease. Additional risk factors may include surgery, hospitalization, pregnancy, the use of corticosteroids and tofacitinib, a JAK inhibitor.The immune system may also attack red blood cells, leading to autoimmune hemolytic anemia. In addition to autoimmune destruction, anemia may occur due to chronic blood loss from rectal bleeding and bone marrow suppression due to inflammation (anemia of chronic disease). Anemic patients can present asymptomatically. However, 75% of individuals exhibit symptoms such as shortness of breath, fatigue, and tachycardia (racing heart). About 1/3rd of patients show signs of jaundice (yellowing of the skin) or darkened urine from loss of bilirubin in urine. A smaller percentage may present with chest pain or a concurrent immune cytopenia, most commonly immune thrombocytopenia (ITP) (CITE WAHA). Osteoporosis may occur related to systemic inflammation, which increases the risk of bone fractures. Clubbing, a deformity of the ends of the fingers, may occur. Amyloidosis may occur, especially with severe and poorly controlled disease, which usually presents with protein in the urine (proteinuria) and nephritic syndrome. Primary sclerosing cholangitis Ulcerative colitis has a significant association with primary sclerosing cholangitis (PSC), a progressive inflammatory disorder of small and large bile ducts. Up to 70-90% of people with primary sclerosing cholangitis have ulcerative colitis. As many as 5% of people with ulcerative colitis may progress to develop primary sclerosing cholangitis. PSC is more common in men, and often begins between 30 and 40 years of age. It can present asymptomatically or exhibit symptoms of itchiness (pruritis) and fatigue. Other symptoms include systemic signs such as fever and night sweats. Such symptoms are often associated with a bacterial episodic version of PSC. Upon physical exam, one may discern enlarged liver contours (hepatomegaly) or enlarged spleen (splenomegaly) as well as areas of excoriation. Yellow coloring of the skin, or jaundice, may also be present due to excess of bile byproduct buildup (bilirubin) from the biliary tract. In diagnosis, lab results often reveal a pattern indicative of biliary disease (cholestatic pattern). This is often displayed by markedly elevated alkaline phosphatase levels and milder or no elevation in liver enzyme levels. Xray results often show bile ducts with thicker walls, areas of dilation or narrowing.In some cases, primary sclerosing cholangitis occurs several years before the bowel symptoms of ulcerative colitis develop. PSC does not parallel the onset, extent, duration, or activity of the colonic inflammation in ulcerative colitis. In addition, colectomy does not have an impact on the course of primary sclerosing cholangitis in individuals with UC. PSC is associated with an increased risk of colorectal cancer and cholangiocarcinoma (bile duct cancer). PSC is a progressive condition, and may result in cirrhosis of the liver. No specific therapy has been proven to affect the long term course of PSC.Other liver-related manifestations of UC include fatty liver disease and autoimmune liver disease. Causes Ulcerative colitis is an autoimmune disease characterized by T-cells infiltrating the colon. No direct causes for UC are known, but factors such as genetics, environment, and an overactive immune system play a role. UC is associated with comorbidities that produce symptoms in many areas of the body outside the digestive system. Genetic factors A genetic component to the cause of UC can be hypothesized based on aggregation of UC in families, variation of prevalence between different ethnicities, genetic markers and linkages. In addition, the identical twin concordance rate is 10%, whereas the dizygotic twin concordance rate is only 3%. Between 8 and 14% of people with ulcerative colitis have a family history of inflammatory bowel disease. In addition, people with a first degree relative with UC have a four-fold increase in their risk of developing the disease.Twelve regions of the genome may be linked to UC, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3, but none of these loci has been consistently shown to be at fault, suggesting that the disorder is influenced by multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease. Some of the putative regions encode transporter proteins such as OCTN1 and OCTN2. Other potential regions involve cell scaffolding proteins such as the MAGUK family. Human leukocyte antigen associations may even be at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.Multiple autoimmune disorders are associated with ulcerative colitis, including celiac disease, psoriasis, lupus erythematosus, rheumatoid arthritis, episcleritis, and scleritis. Ulcerative colitis is also associated with acute intermittent porphyria. Environmental factors Many hypotheses have been raised for environmental factors contributing to the pathogenesis of ulcerative colitis, including diet, breastfeeding and medications. Breastfeeding may have a protective effect in the development of ulcerative colitis. One study of isotretinoin found a small increase in the rate of UC.As the colon is exposed to many dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and Crohns disease. However, current research does not show a link between diet and the development of ulcerative colitis. Few studies have investigated such an association; one study showed no association of refined sugar on the number of people affected of ulcerative colitis. High intake of unsaturated fat and vitamin B6 may enhance the risk of developing ulcerative colitis. Other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. Specifically, sulfur has been investigated as being involved in the cause of ulcerative colitis, but this is controversial. Sulfur restricted diets have been investigated in people with UC and animal models of the disease. The theory of sulfur as an etiological factor is related to the gut microbiota and mucosal sulfide detoxification in addition to the diet.As a result of a class-action lawsuit and community settlement with DuPont, three epidemiologists conducted studies on the population surrounding a chemical plant that was exposed to PFOA at levels greater than in the general population. The studies concluded that there was an association between PFOA exposure and six health outcomes, one of which being ulcerative colitis. Alternative theories Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis, which could indicate higher levels of hydrogen sulfide in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine.Infection by mycobacterium avium, subspecies paratuberculosis, has been proposed as the ultimate cause of both ulcerative colitis and Crohns disease. Pathophysiology An increased amount of colonic sulfate-reducing bacteria has been observed in some people with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. Human colonic mucosa is maintained by the colonic epithelial barrier and immune cells in the lamina propria (see intestinal mucosal barrier). N-butyrate, a short-chain fatty acid, gets oxidized through the beta oxidation pathway into carbon dioxide and ketone bodies. It has been shown that N-butyrate helps supply nutrients to this epithelial barrier. Studies have proposed that hydrogen sulfide plays a role in impairing this beta-oxidation pathway by interrupting the short chain acetyl-CoA dehydrogenase, an enzyme within the pathway. Furthermore, it has been suggested that the protective benefit of smoking in ulcerative colitis is due to the hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the non-toxic isothiocyanate, thereby inhibiting sulfides from interrupting the pathway. An unrelated study suggested that the sulfur contained in red meats and alcohol may lead to an increased risk of relapse for people in remission. Diagnosis The initial diagnostic workup for ulcerative colitis consists of a complete history and physical examination, assessment of signs and symptoms, laboratory tests and endoscopy. Severe UC can exhibit high erythrocyte sedimentation rate (ESR), decreased albumin (a protein produced by the liver), and various changes in electrolytes. As discussed previously, UC patients often also display elevated alkaline phosphatase. Inflammation in the intestine may also cause higher levels of fecal calprotectin or lactoferrin.Specific testing may include the following: A complete blood count is done to check for anemia; thrombocytosis, a high platelet count, is occasionally seen Electrolyte studies and kidney function tests are done, as chronic diarrhea may be associated with hypokalemia, hypomagnesemia and kidney injury. Liver function tests are performed to screen for bile duct involvement: primary sclerosing cholangitis. Imaging such as x-ray or CT scan to evaluate for possible perforation or toxic megacolon Stool culture and Clostridioides difficile stool assay to rule out infectious colitis Inflammatory markers, such as erythrocyte sedimentation rate or C-reactive protein Lower endoscopy to evaluate the rectum and distal large intestine (sigmoidoscopy) or entire colon and end of the small intestine (colonoscopy) for ulcers and inflammationAlthough ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms. Endoscopic The best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohns disease, and assess extent and severity of disease. Endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed.Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). Histologic Biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohns disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). Unlike the transmural inflammation seen in Crohns disease, the inflammation of ulcerative colitis is limited to the mucosa. Laboratory tests Blood and stool tests serve primarily to assess disease severity, level of inflammation and rule out causes of infectious colitis. All individuals with suspected ulcerative colitis should have stool testing to rule out infection.A complete blood count may demonstrate anemia, leukocytosis, or thrombocytosis. Anemia may be caused by inflammation or bleeding. Chronic blood loss may lead to iron deficiency as a cause for anemia, particularly microcytic anemia (small red blood cells), which can be evaluated with a serum ferritin, iron, total iron-binding capacity and transferrin saturation. Anemia may be due to a complication of treatment from azathioprine, which can cause low blood counts, or sulfasalazine, which can result in folate deficiency. Thiopurine metabolites (from azathioprine) and a folate level can help.UC may cause high levels of inflammation throughout the body, which may be quantified with serum inflammatory markers, such as CRP and ESR. However, elevated inflammatory markers are not specific for UC and elevations are commonly seen in other conditions, including infection. In addition, inflammatory markers are not uniformly elevated in people with ulcerative colitis. Twenty five percent of individuals with confirmed inflammation on endoscopic evaluation have a normal CRP level. Serum albumin may also be low related to inflammation, in addition to loss of protein in the GI tract associated with bleeding and colitis. Low serum levels of vitamin D are associated with UC, although the significance of this finding is unclear.Specific antibody markers may be elevated in ulcerative colitis. Specifically, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are found in 70 percent of cases of UC. Antibodies against Saccharomyces cerevisiae may be present, but are more often positive in Crohns disease compared with ulcerative colitis. However, due to poor accuracy of these serolologic tests, they are not helpful in the diagnostic evaluation of possible inflammatory bowel disease.Several stool tests may help quantify the extent of inflammation present in the colon and rectum. Fecal calprotectin is elevated in inflammatory conditions affecting the colon, and is useful in distinguishing irritable bowel syndrome (noninflammatory) from a flare in inflammatory bowel disease. Fecal calprotectin is 88% sensitive and 79% specific for the diagnosis of ulcerative colitis. If the fecal calprotectin is low, the likelihood of inflammatory bowel disease are less than 1 percent. Lactoferrin is an additional nonspecific marker of intestinal inflammation. Imaging Overall, imaging tests, such as x-ray or CT scan, may be helpful in assessing for complications of ulcerative colitis, such as perforation or toxic megacolon. Bowel ultrasound (US) is a cost-effective, well-tolerated, non-invasive and readily available tool for the management of patients with inflammatory bowel disease (IBD), including UC, in clinical practice. Some recent studies demonstrated that US is an accurate tool for assessing disease activity in patients with UC. Imaging is otherwise of limited use in diagnosing ulcerative colitis. Magnetic resonance imaging (MRI) is necessary to diagnose underlying PSC.Abdominal xray is often the test of choice and may display nonspecific findings in cases of mild or moderate ulcerative colitis. In circumstances of severe UC, radiographic findings may include thickening of the mucosa, often termed "thumbprinting," which indicates swelling due to fluid displacement (edema). Other findings may include colonic dilation and stool buildup evidencing constipation.Similar to xray, in mild ulcerative colitis, double contrast barium enema often shows nonspecific findings. Conversely, barium enema may display small buildups of barium in microulcerations. Severe UC can be characterized by various polyps, colonic shortening, loss of haustrae (the small bulging pouches in the colon),and narrowing of the colon. It is important to note that barium enema should not be conducted in patients exhibiting very severe symptoms

Ulcerative colitis

as this may slow or stop stool passage through the colon causing ileus and toxic megacolon.Other methods of imaging include computed tomography (CT) and magnetic resonance imaging (MRI). Both may depict colonic wall thickening but have decreased ability to find early signs of wall changes when compared to barium enema. In cases of severe ulcerative colitis, however, they often exhibit equivalent ability to detect colonic changes.Doppler ultrasound is the last means of imaging that may be used. Similar to the imaging methods mentioned earlier, this may show some thickened bowel wall layers. In severe cases, this may show thickening in all bowel wall layers (transmural thickness). Differential diagnosis Several conditions may present in a similar manner as ulcerative colitis, and should be excluded. Such conditions include: Crohns disease, infectious colitis, nonsteroidal anti-inflammatory drug enteropathy, and irritable bowel syndrome. Alternative causes of colitis should be considered, such as ischemic colitis (inadequate blood flow to the colon), radiation colitis (if prior exposure to radiation therapy), or chemical colitis. Pseudomembranous colitis may occur due to Clostridioides difficile infection following administration of antibiotics. Entamoeba histolytica is a protozoan parasite that causes intestinal inflammation. A few cases have been misdiagnosed as UC with poor outcomes occurring due to the use of corticosteroids.The most common disease that mimics the symptoms of ulcerative colitis is Crohns disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases since their courses and treatments may differ. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis. Crohns disease can be distinguished from ulcerative colitis in several ways. Characteristics that indicate Crohns include evidence of disease around the anus (perianal disease). This includes anal fissures and abscesses as well as fistulas, which are abnormal connections between various bodily structures.Infectious colitis is another condition that may present in similar manner to ulcerative colitis. Endoscopic findings are also oftentimes similar. One can discern whether a patient has infectious colitis by employing tissue cultures and stool studies. Biopsy of the colon is another beneficial test but is more invasive. Other forms of colitis that may present similarly include radiation and diversion colitis. Radiation colitis occurs after irradiation and often affects the rectum or sigmoid colon, similar to ulcerative colitis. Upon histology radiation colitis may indicate eosinophilic infiltrates, abnormal epithelial cells, or fibrosis. Diversion colitis, on the other hand, occurs after portions of bowel loops have been removed. Histology in this condition often shows increased growth of lymphoid tissue. In patients who have undergone transplantation, graft versus host disease may also be a differential diagnosis. This response to transplantation often causes prolonged diarrhea if the colon is affected. Typical symptoms also include rash. Involvement of the upper gastrointestinal tract may lead to difficulty swallowing or ulceration. Upon histology, graft versus host disease may present with crypt cell necrosis and breakdown products within the crypts themselves. Management Standard treatment for ulcerative colitis depends on the extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing remission, which involves relief of symptoms and mucosal healing of the colons lining, and then longer-term treatment to maintain remission and prevent complications. Acute severe ulcerative colitis requires hospitalisation, exclusion of infections, and corticosteroids.For acute stages of the disease, a low fiber diet may be recommended. Medication Ulcerative colitis can be treated with a number of medications, including 5-ASA drugs such as sulfasalazine and mesalazine. Corticosteroids such as prednisone can also be used due to their immunosuppressive and short-term healing properties, but because their risks outweigh their benefits, they are not used long-term in treatment. Immunosuppressive medications such as azathioprine and biological agents such as infliximab and adalimumab are given only if people cannot achieve remission with 5-ASA and corticosteroids. Infliximab, ustekinumab, or vedolizumab are recommended in those with moderate or severe disease.A formulation of budesonide was approved by the U.S. Food and Drug Administration (FDA) for treatment of active ulcerative colitis in January 2013. In 2018, tofacitinib was approved for treatment of moderately to severely active ulcerative colitis in the United States, the first oral medication indicated for long term use in this condition. The evidence on methotrexate does not show a benefit in producing remission in people with ulcerative colitis. Cyclosporine is effective for severe UC and tacrolimus has also shown benefits. Aminosalicylates Sulfasalazine has been a major agent in the therapy of mild to moderate ulcerative colitis for over 50 years. In 1977, it was shown that 5-aminosalicylic acid (5-ASA, mesalazine/mesalamine) was the therapeutically active component in sulfasalazine. Many 5-ASA drugs have been developed with the aim of delivering the active compound to the large intestine to maintain therapeutic efficacy but with reduction of the side effects associated with the sulfapyridine moiety in sulfasalazine. Oral 5-ASA drugs are particularly effective in inducing and in maintaining remission in mild to moderate ulcerative colitis. Rectal suppository, foam or liquid enema formulations of 5-ASA are used for colitis affecting the rectum, sigmoid or descending colon, and have been shown to be effective especially when combined with oral treatment. Biologics Biologic treatments such as the TNF inhibitors infliximab, adalimumab, and golimumab are commonly used to treat people with UC who are no longer responding to corticosteroids. Tofacitinib and vedolizumab can also produce good clinical remission and response rates in UC. Biologics may be used early in treatment (step down approach), or after other treatments have failed to induce remission (step up approach); the strategy should be individualized.Unlike aminosalicylates, biologics can cause serious side effects such as an increased risk of developing extra-intestinal cancers, heart failure; and weakening of the immune system, resulting in a decreased ability of the immune system to clear infections and reactivation of latent infections such as tuberculosis. For this reason, people on these treatments are closely monitored and are often tested for hepatitis and tuberculosis annually. Nicotine Unlike Crohns disease, ulcerative colitis has a lesser chance of affecting smokers than non-smokers. In select individuals with a history of previous tobacco use, resuming low dose smoking may improve signs and symptoms of active ulcerative colitis, but it is not recommended due to the overwhelmingly negative health effects of tobacco. Studies using a transdermal nicotine patch have shown clinical and histological improvement. In one double-blind, placebo-controlled study conducted in the United Kingdom, 48.6% of people with UC who used the nicotine patch, in conjunction with their standard treatment, showed complete resolution of symptoms. Another randomized, double-blind, placebo-controlled, single-center clinical trial conducted in the United States showed that 39% of people who used the patch showed significant improvement, versus 9% of those given a placebo. However, nicotine therapy is generally not recommended due to side effects and inconsistent results. Iron supplementation The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for anemia with blood tests repeated every three months in active disease and annually in quiescent disease. Adequate disease control usually improves anemia of chronic disease, but iron deficiency anemia should be treated with iron supplements. The form in which treatment is administered depends both on the severity of the anemia and on the guidelines that are followed. Some advise that parenteral iron be used first because people respond to it more quickly, it is associated with fewer gastrointestinal side effects, and it is not associated with compliance issues. Others require oral iron to be used first, as people eventually respond and many will tolerate the side effects. Surgery Unlike in Crohns disease, the gastrointestinal aspects of ulcerative colitis can generally be cured by surgical removal of the large intestine, though extraintestinal symptoms may persist. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation, or documented or strongly suspected carcinoma. Surgery is also indicated for people with severe colitis or toxic megacolon. People with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.The removal of the entire large intestine, known as a proctocolectomy, results in a permanent ileostomy – where a stoma is created by pulling the terminal ileum through the abdomen. Intestinal contents are emptied into a removable ostomy bag which is secured around the stoma using adhesive.Another surgical option for ulcerative colitis that is affecting most of the large bowel is called the ileal pouch-anal anastomosis (IPAA). This is a two- or three-step procedure. In a three-step procedure, the first surgery is a sub-total colectomy, in which the large bowel is removed, but the rectum remains in situ, and a temporary ileostomy is made. The second step is a proctectomy and formation of the ileal pouch (commonly known as a "j-pouch"). This involves removing the large majority of the remaining rectal stump and creating a new "rectum" by fashioning the end of the small intestine into a pouch and attaching it to the anus. After this procedure, a new type of ileostomy is created (known as a loop ileostomy) to allow the anastomoses to heal. The final surgery is a take-down procedure where the ileostomy is reversed and there is no longer the need for an ostomy bag. When done in two steps, a proctocolectomy – removing both the colon and rectum – is performed alongside the pouch formation and loop ileostomy. The final step is the same take-down surgery as in the three-step procedure. Time taken between each step can vary, but typically a six- to twelve-month interval is recommended between the first two steps, and a minimum of two to three months is required between the formation of the pouch and the ileostomy take-down.While the ileal pouch procedure removes the need for an ostomy bag, it does not restore normal bowel function. In the months following the final operation, patients typically experience 8–15 bowel movements a day. Over time this number decreases, with many patients reporting four-six bowel movements after one year post-op. While many patients have success with this procedure, there are a number of known complications. Pouchitis, inflammation of the ileal pouch resulting in symptoms similar to ulcerative colitis, is relatively common. Pouchitis can be acute, remitting, or chronic however treatment using antibiotics, steroids, or biologics can be highly effective. Other complications include fistulas, abscesses, and pouch failure. Depending on the severity of the condition, pouch revision surgery may need to be performed. In some cased the pouch may need to be de-functioned or removed and an ileostomy recreated.The risk of cancer arising from a ileal pouch anal anastomosis is low. However, annual surveillance with pouchoscopy may be considered in individuals with risk factors for dysplasia, such as a history of dysplasia or colorectal cancer, a history of PSC, refractory pouchitis, and severely inflamed atrophic pouch mucosa. Bacterial recolonization In a number of randomized clinical trials, probiotics have demonstrated the potential to be helpful in the treatment of ulcerative colitis. Specific types of probiotics such as Escherichia coli Nissle have been shown to induce remission in some people for up to a year. A probiotic named after its gastroenterologist medical doctor inventor, the De Simone Formulation, may be effective in inducing remission in active ulcerative colitis, and may be as effective as 5-ASAs in preventing relapse of quiescent UC. The De Simone Formulation was sold and researched under the brand name VSL#3 until 2016. Since, it has been sold and researched under various regional brand names including Visbiome in the United States and Vivomixx in Europe.Fecal microbiota transplant involves the infusion of human probiotics through fecal enemas. Ulcerative colitis typically requires a more prolonged bacteriotherapy treatment than Clostridium difficile infection to be successful, possibly due to the time needed to heal the ulcerated epithelium. The response of ulcerative colitis is potentially very favorable with one study reporting 67.7% of people experiencing complete remission. Other studies found a benefit from using fecal microbiota transplantation. Alternative medicine A variety of alternative medicine therapies have been used for ulcerative colitis, with inconsistent results. Curcumin (turmeric) therapy, in conjunction with taking the medications mesalamine or sulfasalazine, may be effective and safe for maintaining remission in people with quiescent ulcerative colitis. The effect of curcumin therapy alone on quiescent ulcerative colitis is unknown.Treatments using cannabis or cannabis oil are uncertain. So far, studies havent determined its effectiveness and safety. Abdominal pain management Many interventions have been considered to manage abdominal pain in people with ulcerative colitis, including FODMAPs diet, relaxation training, yoga, kefir diet and stellate ganglion block treatment. It is unclear whether any of these are safe or effective at improving pain or reducing anxiety and depression. Prognosis Poor prognostic factors include: age < 40 years upon diagnosis, extensive colitis, severe colitis on endoscopy, prior hospitalization, elevated CRP and low serum albumin. Progression or remission People with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. People with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. A subset of people experience a course of disease progress rapidly. In these cases, there is usually a failure to respond to medication and surgery often is performed within the first few years of disease onset. People with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of the disease. Several risk factors are associated with eventual need for colectomy, including: prior hospitalization for UC, extensive colitis, need for systemic steroids, young age at diagnosis, low serum albumin, elevated inflammatory markers (CRP & ESR), and severe inflammation seen during colonoscopy. Surgical removal of the large intestine is necessary in some cases. Colorectal cancer The risk of colorectal cancer is significantly increased in people with ulcerative colitis after ten years if involvement is beyond the splenic flexure. People with backwash ileitis might have an increased risk for colorectal carcinoma. Those people with only proctitis usually have no increased risk. It is recommended that people have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity, at one to two year intervals. Mortality People with ulcerative colitis are at similar or perhaps slightly increased overall risk of death compared with the background population. However, the distribution of causes-of-death differs from the general population. Specific risk factors may predict worse outcomes and a higher risk of mortality in people with ulcerative colitis, including: C. difficile infection and cytomegalovirus infection (due to reactivation). Epidemiology Together with Crohns disease, about 11.2 million people were affected as of 2015. Each year, ulcerative colitis newly occurs in 1 to 20 per 100,000 people (incidence), and there are a total of 5-500 per 100,000 individuals with the disease (prevalence). In 2015, a worldwide total of 47,400 people died due to inflammatory bowel disease (UC and Crohns disease). The peak onset is between 30 and 40 years of age, with a second peak of onset occurring in the 6th decade of life. Ulcerative colitis is equally common among men and women. With appropriate treatment the risk of death appears similar to that of the general population. UC has become more common since the 1950s.The geographic distribution of UC and Crohns disease is similar worldwide, with the highest number of new cases a year of UC found in Canada, New Zealand and the United Kingdom. The disease is more common in North America and Europe than other regions. In general, higher rates are seen in northern locations compared to southern locations in Europe and the United States. UC is more common in western Europe compared with eastern Europe. Worldwide, the prevalence of UC varies from 2 - 299 per 100,000 people. Together, ulcerative colitis and Crohns disease affect about a million people in the United States.As with Crohns disease, the rates of UC are greater among Ashkenazi Jews and decreases progressively in other persons of Jewish descent, non-Jewish Caucasians, Africans, Hispanics, and Asians. Appendectomy prior to age 20 for appendicitis and current tobacco use are protective against development of UC. However, former tobacco use is associated with a higher risk of developing the disease. United States As of 2004, the number of new cases of UC in the United States was between 2.2 and 14.3 per 100,000 per year. The number of people affected in the United States in 2004 was between 37 and 246 per 100,000. Canada In Canada, between 1998 and 2000, the number of new cases per year was 12.9 per 100,000 population or 4,500 new cases. The number of people affected was estimated to be 211 per 100,000 or 104,000. United Kingdom In the United Kingdom 10 per 100,000 people newly develop the condition a year while the number of people affected is 243 per 100,000. Approximately 146,000 people in the United Kingdom have been diagnosed with UC. History The first description of ulcerative colitis occurred around the 1850s. Research Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in people with ulcerative colitis. The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of people in the developed world may lead to inflammation. Both helminthic therapy and fecal microbiota transplant induce a characteristic Th2 white cell response in the diseased areas, which was unexpected given that ulcerative colitis was thought to involve Th2 overproduction.Alicaforsen is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human ICAM-1 messenger RNA through Watson-Crick base pair interactions in order to subdue expression of ICAM-1. ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of ulcerative colitis patients, where ICAM-1 over production correlated with disease activity. This suggests that ICAM-1 is a potential therapeutic target in the treatment of ulcerative colitis.Gram positive bacteria present in the lumen could be associated with extending the time of relapse for ulcerative colitis.A series of drugs in development looks to disrupt the inflammation process by selectively targeting an ion channel in the inflammation signaling cascade known as KCa3.1. In a preclinical study in rats and mice, inhibition of KCa3.1 disrupted the production of Th1 cytokines IL-2 and TNF-∝ and decreased colon inflammation as effectively as sulfasalazine.Neutrophil extracellular traps and the resulting degradation of the extracellular matrix have been reported in the colon mucosa in ulcerative colitis patients in clinical remission, indicating the involvement of the innate immune system in the etiology.Fexofenadine, an antihistamine drug used in treatment of allergies, has shown promise in a combination therapy in some studies. Opportunely, low gastrointestinal absorption (or high absorbed drug gastrointestinal secretion) of fexofenadine results in higher concentration at the site of inflammation. Thus, the drug may locally decrease histamine secretion by involved gastrointestinal mast cells and alleviate the inflammation.There is evidence that etrolizumab is effective for ulcerative colitis, with phase 3 trials underway as of 2016. Etrolizumab is a humanized monoclonal antibody that targets he β7 subunit of integrins α4β7 and αEβ7. Etrolizumab decreases lymphocytes trafficking, similar to vedolizumab (another integrin antagonist). A type of leukocyte apheresis, known as granulocyte and monocyte adsorptive apheresis, still requires large-scale trials to determine whether or not it is effective. Results from small trials have been tentatively positive. Notable cases References Further reading External links MedlinePlus ulcerative colitis page

Metaphyseal dysplasia

Metaphyseal dysplasia, or Pyle disease, is a disorder of the bones. It is a rare disease in which the outer part of the shafts of long bones is thinner than normal and there is an increased chance of fractures. Its hallmark feature is an abnormality of the long bones in the arms and legs in which the ends (metaphyses) of the bones are abnormally broad; the shape of the bones resembles a boat oar or paddle. The broad metaphyses are due to enlargement of the spongy inner layer of bone (trabecular bone). Although trabecular bone is expanded, the dense outermost layer of bone (cortical bone) is thinner than normal. As a result, the bones are fragile and fracture easily. The bone abnormalities in the legs commonly cause knock knees (genu valgum) in affected individuals.Other bone abnormalities can also occur in Pyle disease. Affected individuals may have widened collar bones (clavicles), ribs, or bones in the fingers and hands. Dental problems are common in Pyle disease, including delayed appearance (eruption) of permanent teeth and misalignment of the top and bottom teeth (malocclusion). Signs and symptoms It is an autosomal recessive disorder in which mild clinical manifestations contrast with radiological appearances of gross metaphyseal undermodeling. Most patients present with mild genu valgum. The elbows are unable to extend fully. There may be widening of the lower femora and clavicles. Bones can sometimes be fragile, but fracturing is usually not common. Patients may present with dental caries, mandibular prognathism, spinal alignment, and disproportionate limb lengthening. Mental development, physical development, and height are usually normal. Most patients with Pyles diseases will have symptoms that vary from person to person. Symptoms are:5%–29% of people have Delated eruption of teethOther people may have Abnormality of thorax Absent paranasal sinuses Arthralgia Carious teeth Genu valgum Hypoplastic frontal sinuses Limited elbow extension Mandibular prognathia Metaphyseal widening Metaphyseal dysplasia Muscle weakness Platyspondyly Reduced bone mineral density Scoliosis Thickened calvaria Cause Pyle disease is caused by mutations in the SFRP4 gene. This gene provides instructions for making a protein that blocks (inhibits) a process called Wnt signaling, which is involved in the development of several tissues and organs throughout the body. In particular, regulation of Wnt signaling by the SFRP4 protein is critical for normal bone development and remodeling. Bone remodeling is a normal process in which old bone is broken down and new bone is created to replace it. Mutations in the SFRP4 gene are thought to prevent the production of functional SFRP4 protein. The resulting dysregulation of Wnt signaling leads to the bone abnormalities characteristic of Pyle disease.Pyle disease is inherited in an autosomal recessive pattern, which means both copies of the SFRP4 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. While they do not develop the condition, they may have mild abnormalities of the long bones. Diagnosis There are two clinical molecular genetic test that are available to those thought to have Pyle’s Disease. Theses test are; Sequence analysis of the entire coding region and Deletion/duplication analysis. Differential diagnosis Pyle disease may be confused with craniometaphyseal dysplasia. The two, however, are clinically, radiographically, and genetically distinct from one another. Treatment People with Pyle disease are often asymptomatic. Dental anomalies may require orthodontic interventions. Skeletal anomalies may require orthopedic surgery. Epidemiology Pyle disease is thought to be a rare disorder, although its prevalence is unknown. More than 25 cases have been described in the medical literature.It has been described in four German families originating from the same town in Bohemia and in a 7-year-old Japanese girl. Research Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. The study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability.Recently, homozygous mutations in secreted frizzled-related protein 4 gene (SFRP4) gene were found to underlie this condition. Sequencing of coding regions of SFRP4 gene from an 11-year-old female with PYL was performed. A novel homozygous nonsense variant, c.183C>G (p.Y61*) was observed. Segregation analysis in the patient revealed a germline mutation, resulting in reduced protein formation. References == External links ==

Amenorrhea

Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.Amenorrhoea is a symptom with many potential causes. Primary amenorrhea is defined as an absence of secondary sexual characteristics by age 13 with no menarche or normal secondary sexual characteristics but no menarche by 15 years of age. It may be caused by developmental problems, such as the congenital absence of the uterus, failure of the ovary to receive or maintain egg cells, or delay in pubertal development. Secondary amenorrhoea, ceasing of menstrual cycles after menarche, is defined as the absence of menses for three months in a woman with previously normal menstruation, or six months for women with a history of oligomenorrhoea. It is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, premature menopause, intrauterine scar formation, or eating disorders. Pathophysiology Although amenorrhea has multiple potential causes, ultimately, it is the result of hormonal imbalance or an anatomical abnormality.Physiologically, menstruation is controlled by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH acts on the pituitary to stimulate the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH then act on the ovaries to stimulate the production of estrogen and progesterone which, respectively, control the proliferative and secretary phases of the menstrual cycle. Prolactin also influences the menstrual cycle as it suppresses the release of LH and FSH form the pituitary. Similarly, thyroid hormone also affects the menstrual cycle. Low levels of thyroid hormone stimulate the release of TRH from the hypothalamus, which in turn increases both TSH and prolactin release. This increase in prolactin suppresses the release of LH and FSH through a negative feedback mechanism. Amenorrhea can be caused by any mechanism that disrupts this hypothalamic-pituitary-ovarian axis, whether that it be by hormonal imbalance or by disruption of feedback mechanisms. Classification Amenorrhea is classified as either primary or secondary. Primary Amenorrhea Primary amenorrhoea is the absence of menstruation in a woman by the age of 16. Females who have not reached menarche at 14 and who have no signs of secondary sexual characteristics (thelarche or pubarche) are also considered to have primary amenorrhea. Examples of amenorrhea include constitutional delay of puberty, Turner syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. Secondary Amenorrhea Secondary amenorrhoea is defined as the absence of menstruation for three months in a woman with a history of regular cyclic bleeding or six months in a woman with a history of irregular menstrual periods. Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea. Causes Primary amenorrhea Turner syndrome Turner syndrome, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome. Turner syndrome is associated with a wide spectrum of features that vary with each case. However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis. Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, prior to menarche. Therefore, most patients with Turner syndrome will have primary amenorrhea. However, the incidence of spontaneous puberty varies between 8–40% depending on whether or not there is a complete or partial absence of the X chromosome. MRKH MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea. The syndrome is characterized by Müllerian agenesis. In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix. Even though patients with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus. Constitutional delay of puberty Constitutional delay of puberty is a diagnosis of exclusion that is made when the workup for primary amenorrhea does not reveal another cause. Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty. Although more common in boys, girls with delayed puberty present with onset of secondary sexual characteristics after the age of 14, as well as menarche after the age of 16. This may be due to genetics, as some cases of constitutional delay of puberty are familial. Secondary amenorrhea Breastfeeding Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause.Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea. Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion. Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds. Due to this reason, breastfeeding has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited. Diseases of the thyroid Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea.Patients with hypothyroidism frequently present with changes in their menstrual cycle. It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin. Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur.Patients with hyperthyroidism may also present with oligomenorrhea or amenorrhea. Sex hormone binding globulin is increased in hyperthyroid states. This, in turn, increases the total levels of testosterone and estradiol. Increased levels of LH and FSH have also been reported in patients with hyperthyroidism. Hypothalamic and pituitary causes Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea. GnRH is released from the hypothalamus and stimulates the anterior pituitary to release FSH and LH, which in turn stimulate the ovaries to release estrogen and progesterone. Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea.Pituitary adenomas are a common cause of amenorrhea. Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release. Other space occupying pituitary lesions can also cause amenorrhea due to the inhibition of dopamine, an inhibitor of prolactin, due to compression of the pituitary gland. Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4–8% of women worldwide. It is characterized by multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens. Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea. PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche. Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease. Low body weight Women who perform extraneous exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic amenorrhoea. Functional hypothalamic amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise. Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles. The threshold of developing amenorrhoea appears to be dependent on low energy availability rather than absolute weight because a critical minimum amount of stored, easily mobilized energy is necessary to maintain regular menstrual cycles. Amenorrhoea is often associated with anorexia nervosa and other eating disorders. The female athlete triad is when a woman experiences amenorrhoea, disordered eating, and osteoporosis.Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms. Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis. Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH). Low levels of the hormone leptin are also seen in females with low body weight. Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis. Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing. Drug-induced Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use. Hormonal contraceptives that contain only progestogen, like the oral contraceptive Micronor, and especially higher-dose formulations, such as the injectable Depo-Provera, commonly induce this side effect. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using combined oral contraceptive pills (COCP) may experience secondary amenorrhoea as a withdrawal symptom. The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of COCP use and women who experience secondary amenorrhoea because of other reasons. New contraceptive pills which do not have the normal seven days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women. Studies show that women are most likely to experience amenorrhoea after one year of treatment with continuous OCP use.The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhoea as well. Research suggests that anti-psychotic medications effect levels of prolactin, insulin, FSH, LH, and testosterone. Recent research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation. Metformin has been shown to decrease resistance to the hormone insulin, as well as levels of prolactin, testosterone, and luteinizing hormone (LH). Primary ovarian insufficiency Primary ovarian insufficiency (POI) affects 1% of females and is defined as the loss of ovarian function before the age of 40. Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions. Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins. Since the pathogenesis of POI involves the depletion of ovarian reserve, restoration of menstrual cycles typically does not occur in this form of secondary amenorrhea. Diagnosis Primary amenorrhoea Primary amenorrhoea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present. In the absence of secondary sex characteristics, the most common cause of amenorrhoea is low levels of FSH and LH caused by a delay in puberty. Gonadal dysgenesis, often associated with Turner syndrome, or premature ovarian failure may also be to blame. If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16.Evaluation of primary amenorrhea begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. Abnormal TSH levels prompt evaluation for hyper- and hypo-thyroidism with additional thyroid function tests. Elevated prolactin levels prompt evaluation of the pituitary with an MRI to assess for any masses or malignancies. A pelvic ultrasound can also be obtained in the initial evaluation. If a uterus is not present on ultrasound, karyotype analysis and testosterone levels are obtained to assess for MRKH or androgen insensitivity syndrome. If a uterus is present, LH and FSH levels are used to make a diagnosis. Low levels of LH and FSH suggest delayed puberty or functional hypothalamic amenorrhea. Elevated levels of FSH and LH suggest primary ovarian insufficiency, typically due to Turner syndrome. Normal levels of FSH and LH can suggest an anatomical outflow obstruction. Secondary amenorrhea Secondary amenorrheas most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis.Similar to primary amenorrhea, evaluation of secondary amenorrhea also begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. A pelvic ultrasound is also obtained. Abnormal TSH should prompt a thyroid workup with a full thyroid function test panel. Elevated prolactin should be followed with an MRI to look for masses. If LH and FSH are elevated, menopause or primary ovarian insufficiency should be considered. Normal or low levels of FSH and LH prompts further evaluation with patient history and the physical exam. Testosterone, DHEA-S, and 17-hydroxyprogesterone levels should be obtained if there is evidence of excess androgens, such as hirsutism or acne. 17-hydroxyprogesterone is elevated in congenital adrenal hyperplasia. Elevated testosterone and amenorrhea can suggest PCOS. Elevated androgens can also be present in ovarian or adrenal tumors, so additional imaging may also be needed. History of disordered eating or excessive exercise should raise concern for hypothalamic amenorrhea. Headache, vomiting, and vision changes can be signs of a tumor and needs evaluation with MRI. Finally, a history of gynecologic procedures should lead to evaluation of Asherman syndrome with a hysteroscopy or progesterone withdrawal bleeding test. Treatment Treatment for amenorrhea varies based on the underlying condition. Treatment not only focuses on restoring menstruation, if possible, but also preventing additional complications associated with the underlying cause of amenorrhea. Primary amenorrhea In primary amenorrhea, the goal is to continue pubertal development, if possible. For example, most patients with Turner syndrome will be infertile due to gonadal dysgenesis. However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis. In other cases, such as MRKH, hormones do not need to be prescribed since the ovaries are able to function normally. Patients with constitutional delay of puberty may be monitored by an endocrinologist, but definitive treatment may not be needed as there will eventually be progression to normal puberty. Secondary amenorrhea Treatment for secondary amenorrhea varies greatly based on the root cause. Functional hypothalamic amenorrhoea is typically treated by weight gain through increased calorie intake and decreased expenditure. Multidisciplinary treatment with monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches. Although oral contraceptives can cause menses to return, oral contraceptives should not be the initial treatment as they can mask the underlying problem and allow other effects of the eating disorder, like osteoporosis, continue to develop.Patients with hyperprolactinemia are often treated with dopamine agonists to reduce the levels of prolactin and restore menstruation. Surgery and radiation may also be considered if dopamine agonists, such as cabergoline and bromocriptine are ineffective. Once prolactin levels are lowered, the resulting secondary amenorrhea is typically resolved. Similarly, treatment of thyroid abnormalities often resolves the associated amenorrhea. For example, administration of thyroxine in patients with low thyroid levels restored normal menstruation in a majority of patients.Although there is currently no definitive treatment for PCOS, various interventions are used to restore more frequent ovulation in patients. Weight loss and exercise have been associated with a return of ovulation in patients with PCOS due to normalization of androgen levels. Metformin has also been recently studied to regularize menstrual cycles in patients with PCOS. Although the exact mechanism still remains unknown, it is hypothesized that this is due to metformins ability to increase the bodys sensitivity to insulin. Anti-androgen medications, such as spironolactone, can also be used to lower body androgen levels and restore menstruation. Oral contraceptive pills are also often prescribed to patients with secondary amenorrhea due to PCOS in order to regularize the menstrual cycle, although this is due to the suppression of ovulation. References External links Disability Onlines amenorrhoea page Disability Onlines athletic amenorrhoea page Amenorrhea

Hypocalcemia

Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol/L are defined as hypocalcemic. Mildly low levels that develop slowly often have no symptoms. Otherwise symptoms may include numbness, muscle spasms, seizures, confusion, or cardiac arrest.The most common cause for hypocalcemia is iatrogenic hypoparathyroidism. Other causes include other forms of hypoparathyroidism, vitamin D deficiency, kidney failure, pancreatitis, calcium channel blocker overdose, rhabdomyolysis, tumor lysis syndrome, and medications such as bisphosphonates or denosumab. Diagnosis should generally be confirmed with a corrected calcium or ionized calcium level. Specific changes may be seen on an electrocardiogram (ECG).Initial treatment for severe disease is with intravenous calcium chloride and possibly magnesium sulfate. Other treatments may include vitamin D, magnesium, and calcium supplements. If due to hypoparathyroidism, hydrochlorothiazide, phosphate binders, and a low salt diet may also be recommended. About 18% of people who are being treated in hospital have hypocalcemia. Signs and symptoms The neuromuscular symptoms of hypocalcemia are caused by a positive bathmotropic effect (i.e. increased responsiveness) due to the decreased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, reduced calcium lowers the threshold for depolarization. The symptoms can be recalled by the mnemonic "CATs go numb" - convulsions, arrhythmias, tetany, and numbness in the hands and feet and around the mouth. Causes Hypoparathyroidism is a common cause of hypocalcemia. Calcium is tightly regulated by the parathyroid hormone (PTH). In response to low calcium levels, PTH levels rise, and conversely if there are high calcium levels then PTH secretion declines. However, in the setting of absent, decreased, or ineffective PTH hormone, the body loses this regulatory function, and hypocalcemia ensues. Hypoparathyroidism is commonly due to surgical destruction of the parathyroid glands. Hypoparathyroidism may also be due to autoimmune problem. Some causes of hypocalcaemia are as follows: Mechanism Physiologically, blood calcium is tightly regulated within a narrow range for proper cellular processes. Calcium in the blood exists in three primary states: bound to proteins (mainly albumin), bound to anions such as phosphate and citrate, and as free (unbound) ionized calcium; all of these forms are ionised. Only the unbound calcium is physiologically active. Normal blood calcium level is between 8.5 and 10.5 mg/dL (2.12 to 2.62 mmol/L) and that of unbound calcium is 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L). Diagnosis Because a significant portion of calcium is bound to albumin, any alteration in the level of albumin will affect the measured level of calcium. A corrected calcium level based on the albumin level is: Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 * (4.0 - serum albumin [g/dL]). Since calcium is also bound to small anions, it may be more useful to correct total calcium for both albumin and the anion gap. Management Management of this condition includes: Intravenous calcium gluconate 10% can be administered, or if the hypocalcaemia is severe, calcium chloride is given instead. This is only appropriate if the hypocalcemia is acute and has occurred over a relatively short time frame. But if the hypocalcemia has been severe and chronic, then this regimen can be fatal, because there is a degree of acclimatization that occurs. The neuromuscular excitability, cardiac electrical instability, and associated symptoms are then not cured or relieved by prompt administration of corrective doses of calcium, but rather exacerbated. Such rapid administration of calcium would result in effective over correction – symptoms of hypercalcemia would follow. However, in either circumstance, maintenance doses of both calcium and vitamin-D (often as 1,25-(OH)2-D3, i.e. calcitriol) are often necessary to prevent further decline See also Milk fever (hypocalcemia in animals) Calcium deficiency (plant disorder) Hypomagnesemia with secondary hypocalcemia References == External links ==

Carpal tunnel syndrome

Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic compression of the median nerve as it travels through the wrist at the carpal tunnel (IMNCT). Idiopathic means that there is no other disease process contributing to pressure on the nerve. As with most structural issues, it occurs in both hands, and the strongest risk factor is genetics.Other conditions can cause CTS such as wrist fracture or rheumatoid arthritis. After fracture, swelling, bleeding, and deformity compress the median nerve. With rheumatoid arthritis, the enlarged synovial lining of the tendons causes compression. The main symptoms are numbness and tingling in the thumb, index finger, middle finger and the thumb side of the ring finger. People often report pain, but pain without tingling is not characteristic of IMNCT. Rather, the numbness can be so intense that it is described as painful. Symptoms are typically most troublesome at night. Untreated, and over years to decades, IMNCT causes loss of sensibility and weakness and shrinkage (atrophy) of the muscles at the base of the thumb. Work-related factors such as vibration, wrist extension or flexion, hand force, and repetition increase the risk of developing CTS. The only certain risk factor for IMNCT is genetics. All other risk factors are open to debate. It is important to consider IMNCT separately from CTS in diseases such as rheumatoid arthritis.Diagnosis of IMNCT can be made with a high probability based on characteristic symptoms and signs. IMNCT can be measured with electrodiagnostic tests.People wake less often at night if they wear a wrist splint. Injection of corticosteroids may or may not alleviate better than simulated (placebo) injections. There is no evidence that corticosteroid injection alters the natural history of the disease, which seems to be a gradual progression of neuropathy. Surgery to cut the transverse carpal ligament is the only known disease modifying treatment. Anatomy The carpal tunnel is an anatomical compartment located at the base of the palm. Nine flexor tendons and the median nerve pass through the carpal tunnel that is surrounded on three sides by the carpal bones that form an arch. The median nerve provides feeling or sensation to the thumb, index finger, long finger, and half of the ring finger. At the level of the wrist, the median nerve supplies the muscles at the base of the thumb that allow it to abduct, move away from the other four fingers, as well as move out of the plane of the palm. The carpal tunnel is located at the middle third of the base of the palm, bounded by the bony prominence of the scaphoid tubercle and trapezium at the base of the thumb, and the hamate hook that can be palpated along the axis of the ring finger. From the anatomical position, the carpal tunnel is bordered on the anterior surface by the transverse carpal ligament, also known as the flexor retinaculum. The flexor retinaculum is a strong, fibrous band that attaches to the pisiform and the hamulus of the hamate. The proximal boundary is the distal wrist skin crease, and the distal boundary is approximated by a line known as Kaplans cardinal line. This line uses surface landmarks, and is drawn between the apex of the skin fold between the thumb and index finger to the palpated hamate hook. Pathophysiology The median nerve can be compressed by a decrease in the size of the canal, an increase in the size of the contents (such as the swelling of tissue around the flexor tendons), or both. When the pressure builds up inside the tunnel, it damages the median nerve (median neuropathy). As the median neuropathy gets worse, there is loss of sensibility in the thumb, index, middle, and thumb side of the ring finger. As the neuropathy progresses, there may be first weakness, then to atrophy of the muscles of thenar eminence (the flexor pollicis brevis, opponens pollicis, and abductor pollicis brevis). The sensibility of the palm remains normal because the superficial sensory branch of the median nerve branches proximal to the TCL and travels superficial to it.The role of nerve adherence is speculative. Epidemiology IMNCT is estimated to affect one out of ten people during their lifetime and is the most common nerve compression syndrome. There is notable variation in such estimates based on how one defines the problem, in particular whether one studies people presenting with symptoms vs. measurable median neuropathy (IMNCT) whether or not people are seeking care. It accounts for about 90% of all nerve compression syndromes. The best data regarding IMNCT and CTS comes from population-based studies, which demonstrate no relationship to gender, and increasing prevalence (accumulation) with age. Symptoms The characteristic symptom of CTS is numbness, tingling, or burning sensations in the thumb, index, middle, and radial half of the ring finger. These areas process sensation through the median nerve. Numbness or tingling is usually worse with sleep. People tend to sleep with their wrists flexed, which increases pressure on the nerve. Ache and discomfort may be reported in the forearm or even the upper arm, but its relationship to IMNCT is uncertain. Symptoms that are not characteristic of CTS include pain in the wrists or hands, loss of grip strength, minor loss of sleep, and loss of manual dexterity.Median nerve symptoms may arise from compression at the level of the thoracic outlet or the area where the median nerve passes between the two heads of the pronator teres in the forearm, although this is debated. Signs Severe IMNCT is associated with measurable loss of sensibility. Diminished threshold sensibility (the ability to distinguish different amounts of pressure) can be measured using Semmes-Weinstein monofilament testing. Diminished discriminant sensibility can be measured by testing two-point discrimination: the number of millimeters two points of contact need to be separated before you can distinguish them.A person with idiopathic median neuropathy at the carpal tunnel will not have any sensory loss over the thenar eminence (bulge of muscles in the palm of hand and at the base of the thumb). This is because the palmar branch of the median nerve, which innervates that area of the palm, separates from the median nerve and passes over the carpal tunnel.Severe IMNCT is also associated with weakness and atrophy of the muscles at the base of the thumb. People may lose the ability to palmarly abduct the thumb. IMNCT can be detected on examination using one of several maneuvers to provoke paresthesia (a sensation of tingling or "pins and needles" in the median nerve distribution). These so-called provocative signs include: Phalens maneuver. Performed by fully flexing the wrist, then holding this position and awaiting symptoms. A positive test is one that results in paresthesia in the median nerve distribution within sixty seconds. Tinels sign is performed by lightly tapping the median nerve just proximal to flexor retinaculum to elicit paresthesia. Durkan test, carpal compression test, or applying firm pressure to the palm over the nerve for up to 30 seconds to elicit paresthesia. Hand elevation test The hand elevation test is performed by lifting both hands above the head. Paresthesia in the median nerve distribution within 2 minutes is considered positive.Diagnostic performance characteristics such as sensitivity and specificity are reported, but difficult to interpret because of the lack of a consensus reference standard for CTS or IMNCT. Causes Idiopathic Median Neuropathy at the Carpal Tunnel Genetic factors are believed to be the most important determinants of who develops carpal tunnel syndrome due to IMNCT. In other words, your wrist structure seems programmed at birth to develop IMNCT later in life. A genome-wide association study (GWAS) of carpal tunnel syndrome identified 16 genomic loci significantly associated with the disease, including several loci previously known to be associated with human height.Factors that may contribute to symptoms, but have not been experimentally associated with neuropathy include obesity, and Diabetes mellitus . One case-control study noted that individuals classified as obese (BMI > 29) are 2.5 times more likely than slender individuals (BMI < 20) to be diagnosed with CTS. Its not clear whether this association is due to an alteration of pathophysiology, a variation in symptoms, or a variation in care-seeking. Discrete Pathophysiology and Carpal Tunnel Syndrome Hereditary neuropathy with susceptibility to pressure palsies is a genetic condition that appears to increase the probability of developing MNCT. Heterozygous mutations in the gene SH3TC2, associated with Charcot-Marie-Tooth, may confer susceptibility to neuropathy, including CTS.Association between common benign tumors such as lipomas, ganglion, and vascular malformation should be handled with care. Such tumors are very common and overlap with IMNCT is more likely than pressure on the median nerve. Similarly, the degree to which transthyretin amyloidosis-associated polyneuropathy and carpal tunnel syndrome is under investigation. Prior carpal tunnel release is often noted in individuals who later present with transthyretin amyloid-associated cardiomyopathy. There is consideration that bilateral carpal tunnel syndrome could be a reason to consider amyloidosis, timely diagnosis of which could improve heart health. Amyloidosis is rare, even among people with carpal tunnel syndrome (0.55% incidence within 10 years of carpal tunnel release). In the absence of other factors associated with a notable probability of amyloidosis, its not clear that biopsy at the time of carpal tunnel release has a suitable balance between potential harms and potential benefits.Other specific pathophysiologies that can cause median neuropathy via pressure include: Rheumatoid arthritis and other diseases that cause inflammation of the flexor tendons. With severe untreated hypothyroidism, generalized myxedema causes deposition of mucopolysaccharides within both the perineurium of the median nerve, as well as the tendons passing through the carpal tunnel. Association of CTS and IMNCT with lesser degrees of hypothyroidism is questioned. Pregnancy may bring out symptoms in genetically predisposed individuals. Perhaps the changes in hormones and fluid increase pressure temporarily in the carpal tunnel. High progesterone levels and water retention may increase the size of the synovium. Bleeding and swelling from a fracture or dislocation. This is referred to as acute carpal tunnel syndrome. Acromegaly causes excessive secretion of growth hormones. This causes the soft tissues and bones around the carpal tunnel to grow and compress the median nerve.Other considerations Double-crush syndrome is a debated hypothesis that compression or irritation of nerve branches contributing to the median nerve in the neck, or anywhere above the wrist, increases sensitivity of the nerve to compression in the wrist. There is little evidence to support this theory and some concern that it may be used to justify more surgery. Median Neuropathy and Activity Work-related factors that increase risk of CTS include vibration (5.4 effect ratio), hand force (4.2), and repetition (2.3). Exposure to wrist extension or flexion at work increases the risk of CTS by two times. The balance of evidence suggests that keyboard and computer use does not cause CTS.The international debate regarding the relationship between CTS and repetitive hand use (at work in particular) is ongoing. The Occupational Safety and Health Administration (OSHA) has adopted rules and regulations regarding so-called "cumulative trauma disorders" based concerns regarding potential harm from exposure to repetitive tasks, force, posture, and vibration.A review of available scientific data by the National Institute for Occupational Safety and Health (NIOSH) indicated that job tasks that involve highly repetitive manual acts or specific wrist postures were associated with symptoms of CTS, but there was not a clear distinction of paresthesia (appropriate) from pain (inappropriate) and causation was not established. The distinction from work-related arm pains that are not carpal tunnel syndrome was unclear. It is proposed that repetitive use of the arm can affect the biomechanics of the upper limb or cause damage to tissues. It is proposed that postural and spinal assessment along with ergonomic assessments should be considered, based on observation that addressing these factors has been found to improve comfort in some studies although experimental data are lacking and the perceived benefits may not be specific to those interventions. A 2010 survey by NIOSH showed that 2/3 of the 5 million carpal tunnel diagnosed in the US that year were related to work. Women are more likely to be diagnosed with work-related carpal tunnel syndrome than men. Associated conditions A variety of patient factors can lead to CTS, including heredity, size of the carpal tunnel, associated local and systematic diseases, and certain habits. Non-traumatic causes generally happen over a period of time, and are not triggered by one certain event. Many of these factors are manifestations of physiologic aging. Diagnosis There is no consensus reference standard for the diagnosis of carpal tunnel syndrome. A combination of characteristic symptoms (how it feels) and signs (what the clinician finds on exam) are associated with a high probability of IMNCT without electrophysiological testing. Electrodiagnostic testing (electromyography and nerve conduction velocity) can objectively measure and verify median neuropathy.Ultrasound can image and measure the cross sectional diameter of the median nerve, which has some correlation with idiopathic median neuropathy at the carpal tunnel (IMNCT). The role of ultrasound in diagnosis--just as for electrodiagnostic testing--is a matter of debate. EDX cannot fully exclude the diagnosis of CTS due to the lack of sensitivity. A joint report published by the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), the American Academy of Physical Medicine and Rehabilitation (AAPM&R), and the American Academy of Neurology defines practice parameters, standards, and guidelines for EDX studies of CTS based on an extensive critical literature review. This joint review concluded median and sensory nerve conduction studies are valid and reproducible in a clinical laboratory setting and a clinical diagnosis of CTS can be made with a sensitivity greater than 85% and specificity greater than 95%. Given the key role of electrodiagnostic testing in the diagnosis of CTS, The AANEM has issued evidence-based practice guidelines, both for the diagnosis of carpal tunnel syndrome. Electrodiagnostic testing (electromyography and nerve conduction velocity) can objectively verify the median nerve dysfunction. Normal nerve conduction studies, however, do not exclude the diagnosis of CTS. Clinical assessment by history taking and physical examination can support a diagnosis of CTS. If clinical suspicion of CTS is high, treatment should be initiated despite normal electrodiagnostic testing. The role of confirmatory electrodiagnostic testing is debated. The goal of electrodiagnostic testing is to compare the speed of conduction in the median nerve with conduction in other nerves supplying the hand. When the median nerve is compressed, as in IMNCT, it will conduct more slowly than normal and more slowly than other nerves. Compression results in damage to the myelin sheath and manifests as delayed latencies and slowed conduction velocities. There are many electrodiagnostic tests used to make a diagnosis of CTS, but the most sensitive, specific, and reliable test is the Combined Sensory Index (also known as the Robinson index). Electrodiagnosis rests upon demonstrating impaired median nerve conduction across the carpal tunnel in context of normal conduction elsewhere. It is often stated that normal electrodiagnostic studies do not preclude the diagnosis of carpal tunnel syndrome. The rational for this is that a threshold of neuropathy must be reached before study results become abnormal and also that threshold values for abnormality vary. Others contend that idiopathic median neuropathy at the carpal tunnel with normal electrodiagnostic tests would represent very, very mild neuropathy that would be best managed as a normal median nerve. Even more important, notable symptoms with mild disease is strongly associated with unhelpful thoughts and symptoms of worry and despair. Notable CTS with unmeasurable IMNCT should remind clinicians to always consider the whole person, including their mindset and circumstances, in strategies to help people get and stay healthy. Imaging The role of MRI or ultrasound imaging in the diagnosis of idiopathic median neuropathy at the carpal tunnel (IMNCT) is unclear. Their routine use is not recommended. MRI has high sensitivity but low specificity for IMNCT. High signal intensity may suggest accumulation of axonal transportation, myelin sheath degeneration or oedema. Differential diagnosis There are few disorders on the differential diagnosis for carpal tunnel syndrome. Cervical radiculopathy can also cause paresthesia abnormal sensibility in the hands and wrist. The distribution usually follows the nerve root, and the paresthesia may be provoked by neck movement. Electromyography and imaging of the cervical spine can help to differentiate cervical radiculopathy from carpal tunnel syndrome if the diagnosis is unclear. Carpal tunnel syndrome is sometimes applied as a label to anyone with pain, numbness, swelling, or burning in the radial side of the hands or wrists. When pain is the primary symptom, carpal tunnel syndrome is unlikely to be the source of the symptoms.When the symptoms and signs point to atrophy and muscle weakness more than numbness, consider neurodegenerative disorders such as Amyotrophic Lateral Sclerosis or Charcot-Marie Tooth. Prevention There is little or no data to support the concept that activity adjustment prevents carpal tunnel syndrome. The evidence for wrist rest is debated. There is also little research supporting that ergonomics is related to carpal tunnel syndrome. Due to risk factors for hand and wrist dysfunction being multifactorial and very complex it is difficult to assess the true physical factors of carpal tunnel syndrome.Biological factors such as genetic predisposition and anthropometric features are more strongly associated with idiopathic carpal tunnel syndrome than occupational/environmental factors such as hand use. Treatment CTS related to another pathophysiology is addressed by treating that pathology. For instance, disease-modifying medications for rheumatoid arthritis or surgery for traumatic acute carpal tunnel syndrome.Generally accepted treatments include: physiotherapy, steroids either orally or injected locally, splinting, and surgical release of the transverse carpal ligament. Limited evidence suggests that gabapentin is no more effective than placebo for CTS treatment. There is insufficient evidence to recommend therapeutic ultrasound, yoga, acupuncture, low level laser therapy, vitamin B6, myofascial release, and any form of stretch or exercise. Change in activity may include avoiding activities that worsen symptoms.The American Academy of Orthopedic Surgeons recommends proceeding conservatively with a course of nonsurgical therapies tried before release surgery is considered. A different treatment should be tried if the current treatment fails to resolve the symptoms within 2 to 7 weeks. Early surgery with carpal tunnel release is indicated where there is evidence of median nerve denervation or a person elects to proceed directly to surgical treatment. Recommendations may differ when carpal tunnel syndrome is found in association with the following conditions: diabetes mellitus, coexistent cervical radiculopathy, hypothyroidism, polyneuropathy, pregnancy, rheumatoid arthritis, and carpal tunnel syndrome in the workplace. Splint Immobilizations The importance of wrist braces and splints in the carpal tunnel syndrome therapy is known, but many people are unwilling to use braces. In 1993, The American Academy of Neurology recommended a non-invasive treatment for the CTS at the beginning (except for sensitive or motor deficit or grave report at EMG/ENG): a therapy using splints was indicated for light and moderate pathology. Current recommendations generally dont suggest immobilizing braces, but instead activity modification and non-steroidal anti-inflammatory drugs as initial therapy, followed by more aggressive options or specialist referral if symptoms do not improve.Many health professionals suggest that, for the best results, one should wear braces at night. When possible, braces can be worn during the activity primarily causing stress on the wrists. The brace should not generally be used during the day as wrist activity is needed to keep the wrist from becoming stiff and to prevent muscles from weakening. Corticosteroids Corticosteroid injections may provide temporary alleviation of symptoms although they are not clearly better than placebo. This form of treatment is thought to reduce discomfort in those with CTS due to its ability to decrease median nerve swelling. The use of ultrasound while performing the injection is more expensive but leads to faster resolution of CTS symptoms. The injections are done under local anesthesia. This treatment is not appropriate for extended periods, however. In general, local steroid injections are only used until more definitive treatment options can be used. Corticosteroid injections do not appear to slow disease progression. Surgery Release of the transverse carpal ligament is known as "carpal tunnel release" surgery. It is recommended when there is static (constant, not just intermittent) numbness, muscle weakness, or atrophy, and when night-splinting or other palliative interventions no longer alleviate intermittent symptoms. The surgery may be done with local or regional anesthesia with or without sedation, or under general anesthesia. In general, milder cases can be controlled for months to years, but severe cases are unrelenting symptomatically and are likely to result in surgical treatment.Surgery is more beneficial in the short term to alleviate symptoms (up to six months) than wearing an orthosis for a minimum of six weeks. However, surgery and wearing a brace resulted in similar symptom relief in the long term (12–18 month outcomes). Physical therapy An evidence-based guideline produced by the American Academy of Orthopedic Surgeons assigned various grades of recommendation to physical therapy and other nonsurgical treatments. One of the primary issues with physiotherapy is that it attempts to reverse (often) years of pathology inside the carpal tunnel. Self-myofascial ligament stretching can be an easy, do-at-home, treatment to help alleviate symptoms. Self-myofascial stretching involves stretching the carpal ligament for 30 seconds, 6 times a day for about 6 weeks. Many patients report improvements in symptoms such as pain, function, and nerve conduction. Practitioners caution that any physiotherapy such as myofascial release may take weeks of persistent application to effectively manage carpal tunnel syndrome.Again, some claim that pro-active ways to reduce stress on the wrists, which alleviates wrist pain and strain, involve adopting a more ergonomic work and life environment. For example, some have claimed that switching from a QWERTY computer keyboard layout to a more optimised ergonomic layout such as Dvorak was commonly cited as beneficial in early CTS studies; however, some meta-analyses of these studies claim that the evidence that they present is limited.Tendon and nerve gliding exercises appear to be useful in carpal tunnel syndrome.A randomized control trial published in 2017 sought to examine the efficacy of manual therapy techniques for the treatment of carpal tunnel syndrome. The study included a total of 140 individuals diagnosed with carpal tunnel syndrome and the patients were divided into two groups. One group received treatment that consisted of manual therapy. Manual therapy included the incorporation of specified neurodynamic techniques, functional massage, and carpal bone mobilizations. Another group only received treatment through electrophysical modalities. The duration of the study was over the course of 20 physical therapy sessions for both groups. Results of this study showed that the group being treated through manual techniques and mobilizations yielded a 290% reduction in overall pain when compared to reports of pain prior to conducting the study. Total function improved by 47%. Conversely, the group being treated with electrophysical modalities reported a 47% reduction in overall pain with a 9% increase in function. Alternative medicine A 2018 Cochrane review on acupuncture and related interventions for the treatment of carpal tunnel syndrome concluded that, "Acupuncture and laser acupuncture may have little or no effect in the short term on symptoms of carpal tunnel syndrome (CTS) in comparison with placebo or sham acupuncture." It was also noted that all studies had an unclear or high overall risk of bias and that all evidence was of low or very low quality. Prognosis Most people relieved of their carpal tunnel symptoms with conservative or surgical management find minimal residual or "nerve damage". Long-term chronic carpal tunnel syndrome (typically seen in the elderly) can result in permanent "nerve damage", i.e. irreversible numbness, muscle wasting, and weakness. Those that undergo a carpal tunnel release are nearly twice as likely as those not having surgery to develop trigger thumb in the months following the procedure.While outcomes are generally good, certain factors can contribute to poorer results that have little to do with nerves, anatomy, or surgery type. One study showed that mental status parameters or alcohol use yields much poorer overall results of treatment.Recurrence of carpal tunnel syndrome after successful surgery is rare. History The condition known as carpal tunnel syndrome had major appearances throughout the years but it was most commonly heard of in the years following World War II. Individuals who had had this condition have been depicted in surgical literature for the mid-19th century. In 1854, Sir James Paget was the first to report median nerve compression at the wrist in two cases.The first to notice the association between the carpal ligament pathology and median nerve compression appear to have been Pierre Marie and Charles Foix in 1913. They described the results of a postmortem of an 80-year-old man with bilateral carpal tunnel syndrome. They suggested that division of the carpal ligament would be curative in such cases. Putman had previously described a series of 37 patients and suggested a vasomotor origin. The association between the thenar muscle atrophy and compression was noted in 1914. The name "carpal tunnel syndrome" appears to have been coined by Moersch in 1938.In the early 20th century there were various cases of median nerve compression underneath the transverse carpal ligament. Physician George S. Phalen of the Cleveland Clinic identified the pathology after working with a group of patients in the 1950s and 1960s. TreatmentPaget described two cases of carpal tunnel syndrome. The first was due to an injury where a cord had been wrapped around a mans wrist. The second was due to a distal radial fracture. For the first case, Paget performed an amputation of the hand. For the second case Paget recommended a wrist splint – a treatment that is still in use today. Surgery for this condition initially involved the removal of cervical ribs despite Marie and Foixs suggested treatment. In 1933 Sir James Learmonth outlined a method of decompression of the nerve at the wrist. This procedure appears to have been pioneered by the Canadian surgeons Herbert Galloway and Andrew MacKinnon in 1924 in Winnipeg but was not published. Endoscopic release was described in 1988. See also Repetitive strain injury Tarsal tunnel syndrome Ulnar nerve entrapment References External links Carpal Tunnel Syndrome Fact Sheet (National Institute of Neurological Disorders and Stroke) Archived 2016-03-03 at the Wayback Machine NHS website carpal-tunnel.net provides a free to use, validated, online self diagnosis questionnaire for CTS "Carpal Tunnel Syndrome". MedlinePlus. U.S. National Library of Medicine.

Wrist drop

Wrist drop is a medical condition in which the wrist and the fingers cannot extend at the metacarpophalangeal joints. The wrist remains partially flexed due to an opposing action of flexor muscles of the forearm. As a result, the extensor muscles in the posterior compartment remain paralyzed. Forearm anatomy The forearm is the part of the body that extends from the elbow to the wrist and is not to be confused with the arm, which extends from the shoulder to the elbow. The extensor muscles in the forearm are the extensor carpi ulnaris, extensor digiti minimi, extensor digitorum, extensor indicis, extensor carpi radialis brevis, and extensor carpi radialis longus. These extensor muscles are supplied by the posterior interosseous nerve, a branch of the radial nerve. Other muscles in the forearm that are innervated by this nerve are the supinator, extensor pollicis brevis, extensor pollicis longus and abductor pollicis longus. All of these muscles are situated in the posterior half of the forearm (posterior is when it is in its standard anatomical position). Also, the brachioradialis, anconeus, triceps brachii and extensor carpi radialis longus are all innervated by muscular branches of the radial nerve in the arm. Causes Wrist extension is achieved by muscles in the forearm contracting, pulling on tendons that attach distal to (beyond) the wrist. If the tendons, muscles, or nerves supplying these muscles are damaged or otherwise not working as they should be, wrist drop may occur. The following situations may result in wrist drop: Stab wounds to the chest at or below the clavicle–The radial nerve is the terminal branch of the posterior cord of the brachial plexus. A stab wound may damage the posterior cord and result in neurological deficits, including an inability to abduct the shoulder beyond the first 15 degrees, an inability to extend the forearm, reduced ability to supinate the hand, reduced ability to abduct the thumb and sensory loss to the posterior surface of the arm and hand. Broken humerus–The radial nerve can be damaged if the humerus (the bone of the arm) is broken because it runs through the radial groove on the lateral border of this bone along with the deep brachial artery. Lead poisoning–Wrist drop is associated with lead poisoning due to the effect of lead on the radial nerve. Persistent injury–Persistent injury to the nerve is a common cause through either repetitive motion or by applying pressure externally along the route of the radial nerve as in the prolonged use of crutches, extended leaning on the elbows, or regular upper body rope suspension. The colloquial terms for radial nerve palsy are derived from this cause. Correcting dislocated shoulders–Radial nerve palsy can result from the now discredited practice of correcting a dislocated shoulder by putting a foot in the persons armpit and pulling on the arm in attempts to slide the humerus back into the glenoid cavity of the scapula. Neuropathy in the hands and/or arms in patients with rheumatoid arthritis may in rare cases cause wrist drop. "When a joint swells, it can pinch the nerves of sensation that pass next to it. If the swelling irritates the nerve, either because of the inflammation or simply because of pressure, the nerve can send sensations of pain, numbness, and/or tingling to the brain. This is called nerve entrapment. Nerve entrapment most frequently occurs at the wrist (carpal tunnel syndrome) and elbow (ulnar nerve entrapment). A rare form of nerve disease in patients with rheumatoid arthritis that causes numbness and/or tingling is neuropathy. Neuropathy is nerve damage that in people with rheumatoid arthritis can result from inflammation of blood vessels (vasculitis)." Types Types of wrist drop are distinguished by the nerves affected: Weakness of brachioradialis, wrist extension and finger flexion = radial nerve lesion Weakness of finger extension and radial deviation of the wrist on extension = posterior interosseous nerve lesion Weakness of triceps, finger extensors and flexors = c7,8 lesion General weakness of upper limb marked in deltoid, triceps, wrist extension and finger extension = corticospinal lesion Diagnosis The workup for wrist drop frequently includes nerve conduction velocity studies to isolate and confirm the radial nerve as the source of the problem. Other screening tests include the inability to extend the thumb into a "hitchhikers sign". Plain films can help identify bone spurs and fractures that may have injured the nerve. Sometimes MRI imaging is required to differentiate subtle causes. Treatment Initial treatment includes splinting of the wrist for support, along with osteopathic medicine, physiotherapy and occupational therapy. In some cases, surgical removal of bone spurs or other anatomical defects that may be impinging on the nerve might be warranted. If the injury was the result of pressure from prolonged use of improperly fitted crutches or other similar mechanisms of injury, then the symptoms of wrist drop will most likely resolve spontaneously within 8–12 weeks. See also Radial neuropathy References External links clinicalconsiderations at The Anatomy Lesson by Wesley Norman (Georgetown University) William C. Shiel Jr., MD, FACP, FACR. "Rheumatoid Arthritis: 17 Warning Signs of Serious Complications".{{cite web}}: CS1 maint: multiple names: authors list (link)

Autumn

Autumn, also known as fall in American English and Canadian English, is one of the four temperate seasons on Earth. Outside the tropics, autumn marks the transition from summer to winter, in September (Northern Hemisphere) or March (Southern Hemisphere). Autumn is the season when the duration of daylight becomes noticeably shorter and the temperature cools considerably. Day length decreases and night length increases as the season progresses until the Winter Solstice in December (Northern Hemisphere) and June (Southern Hemisphere). One of its main features in temperate climates is the striking change in colour for the leaves of deciduous trees as they prepare to shed. Date definitions Some cultures regard the autumnal equinox as "mid-autumn", while others with a longer temperature lag treat the equinox as the start of autumn. In the English-speaking world of high latitude countries, autumn traditionally began with Lammas Day and ended around Halloween, the approximate mid-points between midsummer, the autumnal equinox, and midwinter. Meteorologists (and Australia and most of the temperate countries in the southern hemisphere) use a definition based on Gregorian calendar months, with autumn being September, October, and November in the northern hemisphere, and March, April, and May in the southern hemisphere. In the higher latitude countries in the Northern Hemisphere, autumn traditionally starts with the September equinox (21 to 24 September) and ends with the winter solstice (21 or 22 December). Popular culture in the United States associates Labor Day, the first Monday in September, as the end of summer and the start of autumn; certain summer traditions, such as wearing white, are discouraged after that date. As daytime and nighttime temperatures decrease, trees change colour and then shed their leaves.Under the traditional East Asian solar term system, autumn starts on or around 8 August and ends on or about 7 November. In Ireland, the autumn months according to the national meteorological service, Met Éireann, are September, October, and November. However, according to the Irish Calendar, which is based on ancient Gaelic traditions, autumn lasts throughout the months of August, September, and October, or possibly a few days later, depending on tradition. In the Irish language, September is known as Meán Fómhair ("middle of autumn") and October as Deireadh Fómhair ("end of autumn"). Persians celebrate the beginning of the autumn as Mehregan to honor Mithra (Mehr). Etymology The word autumn () is derived from Latin autumnus, archaic auctumnus, possibly from the ancient Etruscan root autu- and has within it connotations of the passing of the year. Alternative etymologies include Proto-Indo-European *h₃ewǵ- ("cold") or *h₂sows- ("dry").After the Greek era, the word continued to be used as the Old French word autompne (automne in modern French) or autumpne in Middle English, and was later normalised to the original Latin. In the Medieval period, there are rare examples of its use as early as the 12th century, but by the 16th century, it was in common use. Before the 16th century, harvest was the term usually used to refer to the season, as it is common in other West Germanic languages to this day (cf. Dutch herfst, German Herbst, and Scots hairst). However, as more people gradually moved from working the land to living in towns, the word harvest lost its reference to the time of year and came to refer only to the actual activity of reaping, and autumn, as well as fall, began to replace it as a reference to the season.The alternative word fall for the season traces its origins to old Germanic languages. The exact derivation is unclear, with the Old English fiæll or feallan and the Old Norse fall all being possible candidates. However, these words all have the meaning "to fall from a height" and are clearly derived either from a common root or from each other. The term came to denote the season in 16th-century England, a contraction of Middle English expressions like "fall of the leaf" and "fall of the year". Compare the origin of spring from "spring of the leaf" and "spring of the year".During the 17th century, Englishmen began emigrating to the new North American colonies, and the settlers took the English language with them. While the term fall gradually became nearly obsolete in Britain, it became the more common term in North America.The name backend, a once common name for the season in Northern England, has today been largely replaced by the name autumn. Associations Harvest Association with the transition from warm to cold weather, and its related status as the season of the primary harvest, has dominated its themes and popular images. In Western cultures, personifications of autumn are usually pretty, well-fed females adorned with fruits, vegetables and grains that ripen at this time. Many cultures feature autumnal harvest festivals, often the most important on their calendars. Still-extant echoes of these celebrations are found in the autumn Thanksgiving holiday of the United States and Canada, and the Jewish Sukkot holiday with its roots as a full-moon harvest festival of "tabernacles" (living in outdoor huts around the time of harvest). There are also the many festivals celebrated by indigenous peoples of the Americas tied to the harvest of ripe foods gathered in the wild, the Chinese Mid-Autumn or Moon festival, and many others. The predominant mood of these autumnal celebrations is a gladness for the fruits of the earth mixed with a certain melancholy linked to the imminent arrival of harsh weather. This view is presented in English poet John Keats poem To Autumn, where he describes the season as a time of bounteous fecundity, a time of mellow fruitfulness. In North America, while most foods are harvested during the autumn, foods usually associated with the season include pumpkins (which are integral parts of both Thanksgiving and Halloween) and apples, which are used to make the seasonal beverage apple cider. Melancholia Autumn, especially in poetry, has often been associated with melancholia. The possibilities and opportunities of summer are gone, and the chill of winter is on the horizon. Skies turn grey, the amount of usable daylight drops rapidly, and many people turn inward, both physically and mentally. It has been referred to as an unhealthy season.Similar examples may be found in Irish poet W.B. Yeats poem The Wild Swans at Coole where the maturing season that the poet observes symbolically represents his own ageing self. Like the natural world that he observes, he too has reached his prime and now must look forward to the inevitability of old age and death. French poet Paul Verlaines "Chanson dautomne" ("Autumn Song") is likewise characterised by strong, painful feelings of sorrow. Keats To Autumn, written in September 1819, echoes this sense of melancholic reflection but also emphasises the lush abundance of the season. The song "Autumn Leaves", based on the French song "Les Feuilles mortes", uses the melancholic atmosphere of the season and the end of summer as a metaphor for the mood of being separated from a loved one. Halloween Autumn is associated with Halloween (influenced by Samhain, a Celtic autumn festival), and with it a widespread marketing campaign that promotes it. The Celtic people also used this time to celebrate the harvest with a time of feasting. At the same time though, it was a celebration of death as well. Crops were harvested, livestock were butchered, and Winter was coming.Halloween, 31 October, is in autumn in the northern hemisphere. Television, film, book, costume, home decoration, and confectionery businesses use this time of year to promote products closely associated with such a holiday, with promotions going from late August or early September to 31 October, since their themes rapidly lose strength once the holiday ends, and advertising starts concentrating on Christmas. Other associations In some parts of the northern hemisphere, autumn has a strong association with the end of summer holiday and the start of a new school year, particularly for children in primary and secondary education. "Back to School" advertising and preparations usually occurs in the weeks leading to the beginning of autumn. Thanksgiving Day is a national holiday celebrated in Canada, in the United States, in some of the Caribbean islands and in Liberia. Thanksgiving is celebrated on the second Monday of October in Canada, on the fourth Thursday of November in the United States (where it is commonly regarded as the start of the Christmas and holiday season), and around the same part of the year in other places. Similarly named festival holidays occur in Germany and Japan. Television stations and networks, particularly in North America, traditionally begin their regular seasons in their autumn, with new series and new episodes of existing series debuting mostly during late September or early October (series that debut outside the autumn season are usually known as mid-season replacements). A sweeps period takes place in November to measure Nielsen Ratings. American football is played almost exclusively in the autumn months; at the high school level, seasons run from late August through early November, with some playoff games and holiday rivalry contests being played as late as Thanksgiving. In many American states, the championship games take place in early December. College footballs regular season runs from September through November, while the main professional circuit, the National Football League, plays from September through to early January. Summer sports, such as association football (in Northern America, East Asia, Argentina, and South Africa), Canadian football, stock car racing, tennis, golf, cricket, and professional baseball, wrap up their seasons in early to late autumn; Major League Baseballs championship World Series is popularly known as the "Fall Classic". (Amateur baseball is usually finished by August.) Likewise, professional winter sports, such as ice hockey and basketball, and most leagues of association football in Europe, are in the early stages of their seasons during autumn; American college basketball and college ice hockey play teams outside their athletic conferences during the late autumn before their in-conference schedules begin in winter. The Christian religious holidays of All Saints Day and All Souls Day are observed in autumn in the Northern hemisphere. Easter falls in autumn in the southern hemisphere. The secular celebration of International Workers Day also falls in autumn in the southern hemisphere. Since 1997, Autumn has been one of the top 100 names for girls in the United States.In Indian mythology, autumn is considered to be the preferred season for the goddess of learning Saraswati, who is also known by the name of "goddess of autumn" (Sharada). In Asian mysticism, Autumn is associated with the element of metal, and subsequently with the colour white, the White Tiger of the West, and death and mourning. Tourism Although colour change in leaves occurs wherever deciduous trees are found, coloured autumn foliage is noted in various regions of the world: most of North America, Eastern Asia (including China, Korea, and Japan), Europe, southeast, south, and part of the midwest of Brazil, the forest of Patagonia, eastern Australia and New Zealands South Island. Eastern Canada and New England are famous for their autumnal foliage, and this attracts major tourism (worth billions of US dollars) for the regions. Views of autumn Allegories of autumn in art See also Autumn in New England Diwali References == External links ==

Thoracic aortic aneurysm

A thoracic aortic aneurysm is an aortic aneurysm that presents primarily in the thorax. A thoracic aortic aneurysm is the "ballooning" of the upper aspect of the aorta, above the diaphragm. Untreated or unrecognized they can be fatal due to dissection or "popping" of the aneurysm leading to nearly instant death. Thoracic aneurysms are less common than an abdominal aortic aneurysm. However, a syphilitic aneurysm is more likely to be a thoracic aortic aneurysm than an abdominal aortic aneurysm. This condition is commonly treated via a specialized multidisciplinary approach with both vascular surgeons and cardiac surgeons. Presentation Complications The principal causes of death due to thoracic aneurysmal disease are dissection and rupture. Once rupture occurs, the mortality rate is 50–80%. Most deaths in patients with Marfan syndrome are the result of aortic disease. Causes There are a number of causes, Aneurysms in patients younger than 40 usually involve the ascending aorta due to a weakening of the aortic wall associated with connective tissue disorders like the Marfan and Ehler-Danlos syndromes or congenital bicuspid aortic valve. Younger patients may develop aortic aneurysms of the thoracoabdominal aorta after an aortic dissection. It can also be caused by blunt injury. Atherosclerosis is the principal cause of descending aortic aneurysms, while aneurysms of the aortic arch may be due to dissection, atherosclerosis, or inflammation. Age The diagnosis of thoracic aortic aneurysm usually involves patients in their 60s and 70s. Risk factors Hypertension and cigarette smoking are the most important risk factors, though the importance of genetic factors has been increasingly recognized. Approximately 10 percent of patients may have other family members who have aortic aneurysms. It is also important to note that individuals with a history of aneurysms in other parts of the body have a higher chance of developing a thoracic aortic aneurysm. Diagnosis Thoracic aortic aneurysm is defined as a cross-sectional diameter exceeding the following cutoff: 4.5 cm in the United States 4.0 cm in South KoreaA diameter of 3.5 cm is generally considered dilated. However, average values vary with age and size of the reference population, as well as different segments of the aorta. Screening Guidelines were issued in March 2010 for early detection of thoracic aortic disease, by the American College of Cardiology, the American Heart Association, and other groups. Among the recommendations: First-degree relatives of people with thoracic aortic aneurysm or dissection should have aortic imaging to identify asymptomatic disease. People with symptoms suggestive of thoracic aortic dissection should be routinely evaluated "to establish a pretest risk of disease that can then be used to guide diagnostic decisions." People diagnosed with Marfan syndrome should immediately have an echocardiogram to measure the aorta and followed up six months later to check for aortic enlargement. Treatment The size cut off for aortic aneurysm is crucial to its treatment. A thoracic aorta greater than 4.5 cm is generally defined as aneurysmal, while a size greater than 6 cm is the distinction for treatment, which can be either endovascular or surgical, with the former reserved for pathology at the descending aorta.Indication for surgery may depend upon the size of the aneurysm. Aneurysms in the ascending aorta may require surgery at a smaller size than aneurysms in the descending aorta.Treatment may be via open or via endovascular means. Epidemiology Each year in the United States, some 45,000 people die from diseases of the aorta and its branches. Acute aortic dissection, a life-threatening event due to a tear in the aortic wall, affects 5 to 10 patients per million population each year, most often men between the ages of 50 and 70; of those that occur in women younger than 40, nearly half arise during pregnancy. The majority of these deaths occur as a result of complications of thoracic aneurysmal disease References == External links ==

Esophageal candidiasis

Esophageal candidiasis is an opportunistic infection of the esophagus by Candida albicans. The disease usually occurs in patients in immunocompromised states, including post-chemotherapy and in AIDS. However, it can also occur in patients with no predisposing risk factors, and is more likely to be asymptomatic in those patients. It is also known as candidal esophagitis or monilial esophagitis. Signs and symptoms People with esophageal candidiasis typically present with difficult or painful swallowing. Longstanding esophageal candidiasis can result in weight loss. There is often concomitant thrush in the mouth. Some patients present with esophageal candidiasis as a first presentation of systemic candidiasis. Diagnosis In most cases, the diagnosis is established based on response to therapy. Patients in whom esophageal candidiasis is suspected should receive a brief course of antifungal therapy with fluconazole. If the infection resolves after treatment with fluconazole, then the diagnosis of esophageal candidiasis is made and no further investigation is needed. However, if the infection persists or if there are other factors involved which may warrant further investigation, then patient will undergo an esophagogastroduodenoscopy if it is safe to do so. Endoscopy often reveals classic diffuse raised plaques that characteristically can be removed from the mucosa by the endoscope. Brushing or biopsy of the plaques shows yeast and pseudohyphae by histology that are characteristic of Candida species. Treatment The current first-line treatment is fluconazole, 200 mg. on the first day, followed by daily dosing of 100 mg. for at least 21 days total. Treatment should continue for 14 days after relief of symptoms. Other therapy options include: Nystatin is an effective treatment for mild esophageal candidiasis. It can be used as (swish, do not swallow) treatment for oral candidiasis that occurs with the use of asthma pumps. Oral fluconazole can be used for moderate to severe esophageal candidiasis (and oropharyngeal candidiasis). Other oral triazoles, such as itraconazole Caspofungin, used in refractory or systemic cases Amphotericin, used in refractory or systemic cases Mimidis, K; Papadopoulos, V; Margaritis, V; Thomopoulos, K; Gatopoulou, A; Nikolopoulou, V; Kartalis, G (February 2005). "Predisposing factors and clinical symptoms in HIV-negative patients with Candida oesophagitis: are they always present?". International Journal of Clinical Practice. 59 (2): 210–3. doi:10.1111/j.1742-1241.2004.00249.x. PMID 15854199. References == External links ==

Monocytic leukemia

Monocytic leukemia is a type of myeloid leukemia characterized by a dominance of monocytes in the marrow. When the monocytic cells are predominantly monoblasts, it can be subclassified into acute monoblastic leukemia. Monocytic leukemia is almost always broken down into "acute" and "chronic": acute monocytic leukemia chronic myelomonocytic leukemia References == External links ==

Organ donation

Organ donation is the process when a person allows an organ of their own to be removed and transplanted to another person, legally, either by consent while the donor is alive or dead with the assent of the next of kin. Donation may be for research or, more commonly, healthy transplantable organs and tissues may be donated to be transplanted into another person.Common transplantations include kidneys, heart, liver, pancreas, intestines, lungs, bones, bone marrow, skin, and corneas. Some organs and tissues can be donated by living donors, such as a kidney or part of the liver, part of the pancreas, part of the lungs or part of the intestines, but most donations occur after the donor has died.In 2019, Spain had the highest donor rate in the world at 46.91 per million people, followed by the US (36.88 per million), Croatia (34.63 per million), Portugal (33.8 per million), and France (33.25 per million).As of February 2, 2019, there were 120,000 people waiting for life-saving organ transplants in the US. Of these, 74,897 people were active candidates waiting for a donor. While views of organ donation are positive, there is a large gap between the numbers of registered donors compared to those awaiting organ donations on a global level.To increase the number of organ donors, especially among underrepresented populations, current approaches include the use of optimized social network interventions, exposing tailored educational content about organ donation to target social media users. Every year August 13 is observed as World Organ Donation Day to raising awareness about the importance of organ donation. Process in the United States Organ donors are usually dead at the time of donation, but may be living. For living donors, organ donation typically involves extensive testing before the donation, including psychological evaluation to determine whether the would-be donor understands and consents to the donation. On the day of the donation, the donor and the recipient arrive at the hospital, just like they would for any other major surgery.For dead donors, the process begins with verifying that the person is undoubtedly deceased, determining whether any organs could be donated, and obtaining consent for the donation of any usable organs. Normally, nothing is done until the person has already died, although if death is inevitable, it is possible to check for consent and to do some simple medical tests shortly beforehand, to help find a matching recipient.The verification of death is normally done by a neurologist (a physician specializing in brain function) that is not involved in the previous attempts to save the patients life. This physician has nothing to do with the transplantation process. Verification of death is often done multiple times, to prevent doctors from overlooking any remaining sign of life, however small. After death, the hospital may keep the body on a mechanical ventilator and use other methods to keep the organs in good condition. The donors estate and their families are not charged for any expenses related to the donation. The surgical process depends upon which organs are being donated. The body is normally restored to as normal an appearance as possible, so that the family can proceed with funeral rites and either cremation or burial. The lungs are highly vulnerable to injury and thus the most difficult to preserve, with only 15–25% of donated organs utilized. History The first living organ donor in a successful transplant was Ronald Lee Herrick (1931–2010), who donated a kidney to his identical twin brother in 1954. The lead surgeon, Joseph Murray, and the Nephrologist, John Merril won the Nobel Prize in Physiology or Medicine in 1990 for advances in organ transplantation. The youngest organ donor was a baby with anencephaly, born in 2014, who lived for only 100 minutes and donated his kidneys to an adult with renal failure. The oldest known cornea donor was a 107-year-old Scottish woman, whose corneas were donated after her death in 2016. The oldest known organ donor for an internal organ was a 95-year-old West Virginia man, who donated his liver after he died.The oldest altruistic living organ donor was an 85-year-old woman in Britain, who donated a kidney to a stranger in 2014 after hearing how many people needed to receive a transplant.Researchers were able to develop a novel way to transplant human fetal kidneys into anephric rats to overcome a significant obstacle in impeding human fetal organ transplantations. The human fetal kidneys demonstrated both growth and function within the rats. Brain donation Donated brain tissue is a valuable resource for research into brain function, neurodiversity, neuropathology and possible treatments. Both divergent and healthy control brains are needed for comparison. Brain banks typically source tissue from donors that had directly registered with them before their passing, since organ donor registries focus on tissue meant for transplantation. In the United States the nonprofit Brain Donor Project facilitates this process. Legislation and global perspectives The laws of different countries allow potential donors to permit or refuse donation, or give this choice to relatives. The frequency of donations varies among countries. Consent process The term consent is typically defined as a subject adhering to an agreement of principles and regulations; however, the definition becomes difficult to execute concerning the topic of organ donation, mainly because the subject is incapable of consent due to death or mental impairment. There are two types of consent being reviewed; explicit consent and presumed consent. Explicit consent consists of the donor giving direct consent through proper registration depending on the country. The second consent process is presumed consent, which does not need direct consent from the donor or the next of kin. Presumed consent assumes that donation would have been permitted by the potential donor if permission was pursued. Of possible donors an estimated twenty-five percent of families refuse to donate a loved ones organs. Opt-in versus opt-out As medical science advances, the number of people who could be helped by organ donors increases continuously. As opportunities to save lives increase with new technologies and procedures, the demand for organ donors rises faster than the actual number of donors. In order to respect individual autonomy, voluntary consent must be determined for the individuals disposition of their remains following death. There are two main methods for determining voluntary consent: "opt in" (only those who have given explicit consent are donors) and "opt out" (anyone who has not refused consent to donate is a donor). In terms of an opt-out or presumed consent system, it is assumed that individuals do intend to donate their organs to medical use when they expire. Opt-out legislative systems dramatically increase effective rates of consent for donation as a consequence of the default effect. For example, Germany, which uses an opt-in system, has an organ donation consent rate of 12% among its population, while Austria, a country with a very similar culture and economic development, but which uses an opt-out system, has a consent rate of 99.98%.Opt-out consent, otherwise known as "deemed" consent, support refers to the notion that the majority of people support organ donation, but only a small percentage of the population are actually registered, because they fail to go through the actual step of registration, even if they want to donate their organs at the time of death. This could be resolved with an opt-out system, where many more people would be registered as donors when only those who object consent to donation have to register to be on the non-donation list.For these reasons, countries, such as Wales, have adopted a "soft opt-out" consent, meaning if a citizen has not clearly made a decision to register, then they will be treated as a registered citizen and participate in the organ donation process. Likewise, opt-in consent refers to the consent process of only those who are registered to participate in organ donation. Currently, the United States has an opt-in system, but studies show that countries with an opt-out system save more lives due to more availability of donated organs. The current opt-in consent policy assumes that individuals are not willing to become organ donors at the time of their death, unless they have documented otherwise through organ donation registration.Registering to become an organ donor heavily depends on the attitude of the individual; those with a positive outlook might feel a sense of altruism towards organ donation, while others may have a more negative perspective, such as not trusting doctors to work as hard to save the lives of registered organ donors. Some common concerns regarding a presumed consent ("opt-out") system are sociologic fears of a new system, moral objection, sentimentality, and worries of the management of the objection registry for those who do decide to opt-out of donation. Additional concerns exist with views of compromising the freedom of choice to donate, conflicts with extant religious beliefs and the possibility of posthumous violations of bodily integrity. Even though concerns exist, the United States still has a 95 percent organ donation approval rate. This level of nationwide acceptance may foster an environment where moving to a policy of presumed consent may help solve some of the organ shortage problem, where individuals are assumed to be willing organ donors unless they document a desire to "opt-out", which must be respected.Because of public policies, cultural, infrastructural and other factors, presumed consent or opt-out models do not always translate directly into increased effective rates of donation. The United Kingdom has several different laws and policies for the organ donation process, such as consent of a witness or guardian must be provided to participate in organ donation. This policy is currently being consulted on by Department of Health and Social Care.In terms of effective organ donations, in some systems like Australia (14.9 donors per million, 337 donors in 2011), family members are required to give consent or refusal, or may veto a potential recovery even if the donor has consented. Some countries with an opt-out system like Spain (40.2 donors per million inhabitants), Croatia (40.2 donors/million) or Belgium (31.6 donors/million) have high donor rates, however some countries such as Greece (6 donors/million) maintain low donor rates even with this system. The president of the Spanish National Transplant Organisation has acknowledged Spains legislative approach is likely not the primary reason for the countrys success in increasing the donor rates, starting in the 1990s.Looking to the example of Spain, which has successfully adopted the presumed consent donation system, intensive care units (ICUs) must be equipped with enough doctors to maximize the recognition of potential donors and maintain organs while families are consulted for donation. The characteristic that enables the Spanish presumed consent model to be successful is the resource of transplant coordinators; it is recommended to have at least one at each hospital where opt-out donation is practiced to authorize organ procurement efficiently.Public views are crucial to the success of opt-out or presumed consent donation systems. In a study done to determine if health policy change to a presumed consent or opt-out system would help to increase donors, an increase of 20 to 30 percent was seen among countries who changed their policies from some type of opt-in system to an opt-out system. Of course, this increase must have a great deal to do with the health policy change, but also may be influenced by other factors that could have impacted donor increases.Transplant Priority for Willing Donors, also known as the "donor-priority rule", is a newer method and the first to incorporate a "non-medical" criteria into the priority system to encourage higher donation rates in the opt-in system. Initially implemented in Israel, it allows an individual in need of an organ to move up the recipient list. Moving up the list is contingent on the individual opting-in prior to their need for an organ donation. The policy applies nonmedical criteria when allowing the individual who has previously registered as an organ donor, or family has previously donated an organ, priority over another possible recipient. It must be determined that both recipients have identical medical needs prior to moving a recipient up the list. While incentives like this in the opt-in system do help raise donation rates, they are not as successful in doing so as the opt-out, presumed consent default policies for donation. Argentina On November 30, 2005, the Congress introduced an opt-out policy on organ donation, where all people over 18 years of age will be organ donors unless they or their family state otherwise. The law was promulgated on December 22, 2005, as "Law 26,066".On July 4, 2018, the Congress passed a law removing the family requirement, making the organ donor the only person that can block donation. It was promulgated on July 4, 2018, as Law Justina or "Law 27,447". Brazil A campaign by Sport Club Recife has led to waiting lists for organs in north-east Brazil to drop almost to zero; while according to the Brazilian law the family has the ultimate authority, the issuance of the organ donation card and the ensuing discussions have however eased the process. Canada In 2001, the Government of Canada announced the formation of the Canadian Council for Donation and Transplantation, whose purpose would be to advise the Conference of Deputy Ministers of Health on activities relating to organ donation and transplantation. The deputy ministers of health for all provinces and territories with the exception of Québec decided to transfer the responsibilities of the Canadian Council for Donation and Transplantation to Canadian Blood Services.In Québec, an organization called Transplant Québec is responsible for managing all organ donation; Héma-Québec is responsible for tissue donation. Consent for organ donation by an individual is given by either registering with the organ donation registry established by the Chambre des notaires du Québec, signing and affixing the sticker to the back of ones health insurance card, or registering with either Régie de lassurance maladie du Québec or Registre des consentements au don dorganes et de tissus. In 2017, the majority of transplants completed were kidney transplants. Canadian Blood Services has a program called the kidney paired donation, where transplant candidates are matched with compatible living donors from all over Canada. It also gives individuals an opportunity to be a living donor for an anonymous patient waiting for a transplant. As of December 31, 2017, there were 4,333 patients on the transplant waitlist. In 2017, there were a total of 2,979 transplants, including multi-organ transplants; 242 patients died while on the waitlist. 250 Canadians die on average waiting for transplant organs every year.Each province has different methods and registries for intent to donate organs or tissues as a deceased donor. In some provinces, such as Newfoundland and Labrador and New Brunswick organ donation registration is completed by completing the "Intent to donate" section when applying or renewing ones provincial medical care. In Ontario, one must be 16 years of age to register as an organ and tissue donor and register with ServiceOntario. Alberta requires that a person must be 18 years of age or older and register with the Alberta Organ and Tissue Donation Registry. Opt-out donation in Canada Nova Scotia, Canada, is the first jurisdiction in North America that will be introducing an automatic organ donation program unless residents opt out; this is known as presumed consent. The Human Organ and Tissue Act was introduced on April 2, 2019. When the new legislation is in effect, all people who have been Nova Scotia residents for a minimum of 12 consecutive months, with appropriate decision-making capacity and are over 19 years of age are considered potential donors and will be automatically referred to donation programs if they are determined to be good candidates. In the case of persons under 19 years of age and people without appropriate decision-making capacity, they will only be considered as organ donors if their parent, guardian or decision-maker opts them into the program. The new legislation is scheduled to take effect in mid to late 2020, and will not be applicable to tourists visiting Nova Scotia or post-secondary students from other provinces or countries Chile On January 6, 2010, the "Law 20,413" was promulgated, introducing an opt-out policy on organ donation, where all people over 18 years of age will be organ donors unless they state their negative. Colombia On August 4, 2016, the Congress passed the "Law 1805", which introduced an opt-out policy on organ donation where all people will be organ donors unless they state their negative. The law came into force on February 4, 2017. Europe Within the European Union, organ donation is regulated by member states. As of 2010, 24 European countries have some form of presumed consent (opt-out) system, with the most prominent and limited opt-out systems in Spain, Austria, and Belgium yielding high donor rates. Spain had the highest donor rate in the world, 46.9 per million people in the population, in 2017. This is attributed to multiple factors in the Spanish medical system, including identification and early referral of possible donors, expanding criteria for donors and standardised frameworks for transplantation after circulatory death.In England organ donation is voluntary and no consent is presumed. Individuals who wish to donate their organs after death can use the Organ Donation Register, a national database. The government of Wales became the first constituent country in the UK to adopt presumed consent in July 2013. The opt-out organ donation scheme in Wales went live on December 1, 2015, and is expected to increase the number of donors by 25%. In 2008, the UK discussed whether to switch to an opt-out system in light of the success in other countries and a severe British organ donor shortfall. In Italy if the deceased neither allowed nor refused donation while alive, relatives will pick the decision on his or her behalf despite a 1999 act that provided for a proper opt-out system. In 2008, the European Parliament overwhelmingly voted for an initiative to introduce an EU organ donor card in order to foster organ donation in Europe.Landstuhl Regional Medical Center (LRMC) has become one of the most active organ donor hospitals in all of Germany, which otherwise has one of the lowest organ donation participation rates in the Eurotransplant organ network. LRMC, the largest U.S. military hospital outside the United States, is one of the top hospitals for organ donation in the Rhineland-Palatinate state of Germany, even though it has relatively few beds compared to many German hospitals. According to the German organ transplantation organization, Deutsche Stiftung Organtransplantation (DSO), 34 American military service members who died at LRMC (roughly half of the total number who died there) donated a total of 142 organs between 2005 and 2010. In 2010 alone, 10 of the 12 American service members who died at LRMC were donors, donating a total of 45 organs. Of the 205 hospitals in the DSOs central region—which includes the large cities of Frankfurt and Mainz—only six had more organ donors than LRMC in 2010.Scotland conforms to the Human Tissue Authority Code of Practice, which grants authority to donate organs, instead of consent of the individual. This helps to avoid conflict of implications and contains several requirements. In order to participate in organ donation, one must be listed on the Organ Donor Registry (ODR). If the subject is incapable of providing consent, and is not on the ODR, then an acting representative, such as a legal guardian or family member can give legal consent for organ donation of the subject, along with a presiding witness, according to the Human Tissue Authority Code of Practice. Consent or refusal from a spouse, family member, or relative is necessary for a subject is incapable. Austria participates in the "opt-out" consent process, and have laws that make organ donation the default option at the time of death. In this case, citizens must explicitly "opt out" of organ donation. Yet in countries such as U.S.A. and Germany, people must explicitly "opt in" if they want to donate their organs when they die. In Germany and Switzerland there are Organ Donor Cards available.In May 2017, Ireland began the process of introducing an "opt-out" system for organ donation. Minister for Health, Simon Harris, outlined his expectations to have the Human Tissue Bill passed by the end of 2017. This bill would put in place the system of "presumed consent".The Mental Capacity Act is another legal policy in place for organ donation in the UK. The act is used by medical professionals to declare a patients mental capacity. The act claims that medical professionals are to "act in a patients best interest", when the patient is unable to do so. India India has a fairly well developed corneal donation programme; however, donation after brain death has been relatively slow to take off. Most of the transplants done in India are living related or unrelated transplants. To curb organ commerce and promote donation after brain death the government enacted a law called "The Transplantation of Human Organs Act" in 1994 that brought about a significant change in the organ donation and transplantation scene in India. Many Indian states have adopted the law and in 2011 further amendment of the law took place. Despite the law there have been stray instances of organ trade in India and these have been widely reported in the press. This resulted in the amendment of the law further in 2011. Deceased donation after brain death have slowly started happening in India and 2012 was the best year for the programme. Source the Indian Transplant News Letter of the MOHAN FoundationThe year 2013 has been the best yet for deceased organ donation in India. A total of 845 organs were retrieved from 310 multi-organ donors resulting in a national organ donation rate of 0.26 per million population(Table 2). * ODR (pmp) – Organ Donation Rate (per million population) In the year 2000 through the efforts of an NGO called MOHAN Foundation state of Tamil Nadu started an organ sharing network between a few hospitals. This NGO also set up similar sharing network in the state of Andhra Pradesh and these two states were at the forefront of deceased donation and transplantation programme for many years. As a result, retrieval of 1,033 organs and tissues were facilitated in these two states by the NGO.Similar sharing networks came up in the states of Maharashtra and Karnataka; however, the numbers of deceased donation happening in these states were not sufficient to make much impact. In 2008, the Government of Tamil Nadu put together government orders laying down procedures and guidelines for deceased organ donation and transplantation in the state. These brought in almost thirty hospitals in the programme and has resulted in significant increase in the donation rate in the state. With an organ donation rate of 1.15 per million population, Tamil Nadu is the leader in deceased organ donation in the country. The small success of Tamil Nadu model has been possible due to the coming together of both government and private hospitals, NGOs and the State Health department. Most of the deceased donation programmes have been developed in southern states of India. The various such programmes are as follows: In the year 2012 besides Tamil Nadu other southern states too did deceased donation transplants more frequently. An online organ sharing registry for deceased donation and transplantation is used by the states of Tamil Nadu and Kerala. Both these registries have been developed, implemented and maintained by MOHAN Foundation. However. National Organ and Tissue Transplant Organization (NOTTO) is a National level organization set up under Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India and only official organization. Organ selling is legally banned in Asia. Numerous studies have documented that organ vendors have a poor quality of life (QOL) following kidney donation. However, a study done by Vemuru reddy et al shows a significant improvement in Quality of life contrary to the earlier belief. Live related renal donors have a significant improvement in the QOL following renal donation using the WHO QOL BREF in a study done at the All India Institute of Medical Sciences from 2006 to 2008. The quality of life of the donor was poor when the graft was lost or the recipient died.In India, there are six types of life saving organs that can be donated to save the life of a patient. These include Kidneys, Liver, Heart, Lungs, Pancreas and Intestine. Off late, uterus transplant has also been started in India. However, uterus is not a life saving organ as per the Transplantation of Human Organs Act (2011). Recently a scoring system, Seth-Donation of Organs and Tissues (S-DOT) score, has been developed to assess hospitals for best practices in tissue donation and organ donation after brain death. Iran Only one country, Iran has eliminated the shortage of transplant organs—and only Iran has a working and legal payment system for organ donation. It is also the only country where organ trade is legal. The way their system works is, if a patient does not have a living relative or who are not assigned an organ from a deceased donor, apply to the nonprofit Dialysis and Transplant Patients Association (Datpa). The association establishes potential donors, those donors are assessed by transplant doctors who are not affiliated with the Datpa association. The government gives a compensation of $1,200 to the donors and aid them a year of limited health-insurance. Additionally, working through Datpa, kidney recipients pay donors between $2,300 and $4,500. Importantly, it is illegal for the medical and surgical teams involved or any middleman to receive payment. Charity donations are made to those donors whose recipients are unable to pay. The Iranian system began in 1988 and eliminated the shortage of kidneys by 1999. Within the first year of the establishment of this system, the number of transplants had almost doubled; nearly four-fifths were from living unrelated sources.[55] Nobel Laureate economist Gary Becker and Julio Elias estimated that a payment of $15,000 for living donors would alleviate the shortage of kidneys in the U.S. Israel Since 2008, signing an organ donor card in Israel has provided a potential medical benefit to the signer. If two patients require an organ donation and have the same medical need, preference will be given to the one that had signed an organ donation card. (This policy was nicknamed "Dont give, dont get".) Organ donation in Israel increased after 2008. Japan The rate of organ donation in Japan is significantly lower than in Western countries. This is attributed to cultural reasons, some distrust of western medicine, and a controversial organ transplantation in 1968 that provoked a ban on cadaveric organ donation that would last thirty years. Organ donation in Japan is regulated by a 1997 organ transplant law, which defines "brain death" and legalized organ procurement from brain dead donors. Netherlands The Netherlands sends everyone living in the country a postcard when they turn 18 (and everyone living in the country when the 2020 law came into effect), and one reminder if they do not reply. They may choose to donate, not to donate, to delegate the choice to family, or to name a specific person. If they do not reply to either notice, they are considered a donor by default. A family cannot object unless there is reason to show the person would not have wanted to donate. If a person cannot be found in the national donor registry, because they are travelling from another country or because they are undocumented, their organs are not harvested without family consent. Organs are not harvested from people who die an unnatural death without the approval of the local attorney general. New Zealand New Zealand law allows live donors to participate in altruistic organ donation only. In the five years to 2018, there were 16 cases of liver donation by live donors and 381 cases of kidney donation by live donors. New Zealand has low rates of live donation, which could be due to the fact that it is illegal to pay someone for their organs. The Human Tissue Act 2008 states that trading in human tissue is prohibited, and is punishable by a fine of up to $50,000 or a prison term of up to 1 year. The Compensation for Live Organ Donors Act 2016, which came into force in December 2017, allows live organ donors to be compensated for lost income for up to 12 weeks post-donation.New Zealand law also allows for organ donation from deceased individuals. In the five years to 2018, organs were taken from 295 deceased individuals. Everyone who applies for a drivers licence in New Zealand indicates whether or not they wish to be a donor if they die in circumstances that would allow for donation. The question is required to be answered for the application to be processed, meaning that the individual must answer yes or no, and does not have the option of leaving it unanswered. However, the answer given on the drivers license does not constitute informed consent, because at the time of drivers license application not all individuals are equipped to make an informed decision regarding whether to be a donor, and it is therefore not the deciding factor in whether donation is carried out or not. It is there to simply give indication of the persons wishes. Family

Organ donation

must agree to the procedure for donation to take place.A 2006 bill proposed setting up an organ donation register where people can give informed consent to organ donations and clearly state their legally binding wishes. However, the bill did not pass, and there was condemnation of the bill from some doctors, who said that even if a person had given express consent for organ donation to take place, they would not carry out the procedure in the presence of any disagreement from grieving family members.The indigenous population of New Zealand also have strong views regarding organ donation. Many Maori people believe organ donation is morally unacceptable due to the cultural need for a dead body to remain fully intact. However, because there is not a universally recognised cultural authority, no one view on organ donation is universally accepted in the Maori population. They are, however, less likely to accept a kidney transplant than other New Zealanders, despite being overrepresented in the population receiving dialysis. South Korea In South Korea, the 2006 provision of the Organ Transplant Act introduced a monetary incentive equivalent to US$4,500 to the surviving family of brain-death donors; the reward is intended as consolation and compensation for funeral expenses and hospital fees. Sri Lanka Organ donation in Sri Lanka was ratified by the Human Tissue Transplantation Act No. 48 of 1987. Sri Lanka Eye Donation Society, a non-governmental organization established in 1961 has provided over 60,000 corneas for corneal transplantation, for patients in 57 countries. It is one of the major suppliers of human eyes to the world, with a supply of approximately 3,000 corneas per year. United Kingdom Wales Since December 2015, Human Transplantation (Wales) Act 2013 passed by the Welsh Government has enabled an opt-out organ donation register, the first country in the UK to do so. The legislation is deemed consent, whereby all citizens are considered to have no objection to becoming a donor, unless they have opted out on this register. England and Scotland Englands Organ Donation Act, also known as Max and Keiras law, came into effect in May 2020. It means adults in England will be automatically be considered potential donors unless they chose to opt out or are excluded. As of March 2021 Scotland also has an opt-out system. Dependencies The British Crown dependency of Jersey moved to an opt-out register on July 1, 2019. United States Over 121,000 people in need of an organ are on the U.S. government waiting list. This crisis within the United States is growing rapidly because on average there are only 30,000 transplants performed each year. More than 8,000 people die each year from lack of a donor organ, an average of 22 people a day. Between the years 1988 and 2006 the number of transplants doubled, but the number of patients waiting for an organ grew six times as large.In the past presumed consent was urged to try to decrease the need for organs. The Uniform Anatomical Gift Act of 1987 was adopted in several states, and allowed medical examiners to determine if organs and tissues of cadavers could be donated. By the 1980s, several states adopted different laws that allowed only certain tissues or organs to be retrieved and donated, some allowed all, and some did not allow any without consent of the family. In 2006 when the UAGA was revised, the idea of presumed consent was abandoned. In the United States today, organ donation is done only with consent of the family or donator themselves.According to economist Alex Tabarrok, the shortage of organs has increased the use of so-called expanded criteria organs, or organs that used to be considered unsuitable for transplant. Five patients that received kidney transplants at the University of Maryland School of Medicine developed cancerous or benign tumors which had to be removed. The head surgeon, Dr. Michael Phelan, explained that "the ongoing shortage of organs from deceased donors, and the high risk of dying while waiting for a transplant, prompted five donors and recipients to push ahead with the surgery." Several organizations such as the American Kidney Fund are pushing for opt-out organ donation in the United States. Donor Leave Laws In addition to their sick and annual leave, federal executive agency employees are entitled to 30 days paid leave for organ donation. Thirty-two states (excluding only Alabama, Connecticut, Florida, Kentucky, Maine, Michigan, Montana, Nebraska, Nevada, New Hampshire, New Jersey, North Carolina, Pennsylvania, Rhode Island, South Dakota, Tennessee, Vermont, and Wyoming) and the District of Columbia also offer paid leave for state employees. Five states (California, Hawaii, Louisiana, Minnesota, and Oregon) require certain private employers to provide paid leave for employees for organ or bone marrow donation, and seven others (Arkansas, Connecticut, Maine, Nebraska, New York, South Carolina, and West Virginia) either require employers to provide unpaid leave, or encourage employers to provide leave, for organ or bone marrow donation.A bill in the US House of Representatives, the Living Donor Protection Act (introduced in 2016, then reintroduced in 2017), would amend the Family and Medical Leave Act of 1993 to provide leave under the act for an organ donor. If successful, this new law would permit "eligible employee" organ donors to receive up to 12 work weeks of leave in a 12-month period. Tax incentives Nineteen US states and the District of Columbia provide tax incentives for organ donation. The most generous state tax incentive is Utahs tax credit, which covers up to $10,000 of unreimbursed expenses (travel, lodging, lost wages, and medical expenses) associated with organ or tissue donation. Idaho (up to $5,000 of unreimbursed expenses) and Louisiana (up to $7,500 of 72% of unreimbursed expenses) also provide donor tax credits. Arkansas, the District of Columbia, Louisiana and Pennsylvania provide tax credits to employers for wages paid to employees on leave for organ donation. Thirteen states (Arkansas, Georgia, Iowa, Massachusetts, Mississippi, New Mexico, New York, North Dakota, Ohio, Oklahoma, Rhode Island and Wisconsin) have a tax deduction for up to $10,000 of unreimbursed costs, and Kansas and Virginia offer a tax deduction for up to $5,000 of unreimbursed costs.States have focused their tax incentives on unreimbursed costs associated with organ donation to ensure compliance with the National Organ Transplant Act of 1984. NOTA prohibits, "any person to knowingly acquire, receive, or otherwise transfer any human organ for valuable consideration for use in human transplantation." However, NOTA exempts, "the expenses of travel, housing, and lost wages incurred by the donor of a human organ in connection with the donation of the organ," from its definition of "valuable consideration".While offering income tax deductions has been the preferred method of providing tax incentives, some commentators have expressed concern that these incentives provide disproportionate benefits to wealthier donors. Tax credits, on the other hand, are perceived as more equitable since the after tax benefit of the incentive is not tied to the marginal tax rate of the donor.Additional tax favored approaches have been proposed for organ donation, including providing: tax credits to the families of deceased donors (seeking to encourage consent), refundable tax credits (similar to the earned income credit) to provide greater tax equity among potential donors, and charitable deductions for the donation of blood or organs. Other financial incentives As stated above, under the National Organ Transplant Act of 1984, granting monetary incentives for organ donation is illegal in the United States. However, there has been some discussion about providing fixed payment for potential live donors. In 1988, regulated paid organ donation was instituted in Iran and, as a result, the renal transplant waiting list was eliminated. Critics of paid organ donation argue that the poor and vulnerable become susceptible to transplant tourism. Travel for transplantation becomes transplant tourism if the movement of organs, donors, recipients or transplant professionals occurs across borders and involves organ trafficking or transplant commercialism. Poor and underserved populations in underdeveloped countries are especially vulnerable to the negative consequences of transplant tourism because they have become a major source of organs for the transplant tourists that can afford to travel and purchase organs.In 1994 a law was passed in Pennsylvania which proposed to pay $300 for room and board and $3,000 for funeral expenses to an organ donors family. Developing the program was an eight-year process; it is the first of its kind. Procurement directors and surgeons across the nation await the outcomes of Pennsylvanias program. There have been at least nineteen families that have signed up for the benefit. Due to investigation of the program, however, there has been some concern whether the money collected is being used to assist families. Nevertheless, funeral aids to induce post-mortem organ donation have also received support from experts and the general public, as they present more ethical values, such as honoring the deceased donor, and potentially increase donation willingness.Some organizations, such as the National Kidney Foundation, oppose financial incentives associated with organ donation claiming, "Offering direct or indirect economic benefits in exchange for organ donation is inconsistent with our values as a society." One argument is it will disproportionately affect the poor. The $300–3,000 reward may act as an incentive for poorer individuals, as opposed to the wealthy who may not find the offered incentives significant. The National Kidney Foundation has noted that financial incentives, such as this Pennsylvania statute, diminish human dignity. Bioethical issues Deontological Deontological issues are issues about whether a person has an ethical duty or responsibility to take an action. Nearly all scholars and societies around the world agree that voluntarily donating organs to sick people is ethically permissible. Although nearly all scholars encourage organ donation, fewer scholars believe that all people are ethically required to donate their organs after death. Similarly, nearly all religions support voluntary organ donation as a charitable act of great benefit to the community. Certain small faiths such as Jehovah Witnesses and Shinto are opposed to organ donation based upon religious teachings; for Jehovah Witnesses this opposition is absolute whereas there exists increasing flexibility amongst Shinto scholars. The Roma People, are also often opposed to organ donation based on prevailing spiritual beliefs and not religious views per se. Issues surrounding patient autonomy, living wills, and guardianship make it nearly impossible for involuntary organ donation to occur. From the standpoint of deontological ethics, the primary issues surrounding the morality of organ donation are semantic in nature. The debate over the definitions of life, death, human, and body is ongoing. For example, whether or not a brain-dead patient ought to be kept artificially animate in order to preserve organs for donation is an ongoing problem in clinical bioethics. In addition, some have argued that organ donation constitutes an act of self-harm, even when an organ is donated willingly.Further, the use of cloning to produce organs with a genotype identical to the recipient is a controversial topic, especially considering the possibility for an entire person to be brought into being for the express purpose of being destroyed for organ procurement. While the benefit of such a cloned organ would be a zero-percent chance of transplant rejection, the ethical issues involved with creating and killing a clone may outweigh these benefits. However, it may be possible in the future to use cloned stem-cells to grow a new organ without creating a new human being. A relatively new field of transplantation has reinvigorated the debate. Xenotransplantation, or the transfer of animal (usually pig) organs into human bodies, promises to eliminate many of the ethical issues, while creating many of its own. While xenotransplantation promises to increase the supply of organs considerably, the threat of organ transplant rejection and the risk of xenozoonosis, coupled with general anathema to the idea, decreases the functionality of the technique. Some animal rights groups oppose the sacrifice of an animal for organ donation and have launched campaigns to ban them. Teleological On teleological or utilitarian grounds, the moral status of "black market organ donation" relies upon the ends, rather than the means. In so far as those who donate organs are often impoverished and those who can afford black market organs are typically well-off, it would appear that there is an imbalance in the trade. In many cases, those in need of organs are put on waiting lists for legal organs for indeterminate lengths of time—many die while still on a waiting list. Organ donation is fast becoming an important bioethical issue from a social perspective as well. While most first-world nations have a legal system of oversight for organ transplantation, the fact remains that demand far outstrips supply. Consequently, there has arisen a black market trend often referred to as transplant tourism. The issues are weighty and controversial. On the one hand are those who contend that those who can afford to buy organs are exploiting those who are desperate enough to sell their organs. Many suggest this results in a growing inequality of status between the rich and the poor. On the other hand, are those who contend that the desperate should be allowed to sell their organs and that preventing them from doing so is merely contributing to their status as impoverished. Further, those in favor of the trade hold that exploitation is morally preferable to death, and in so far as the choice lies between abstract notions of justice on the one hand and a dying person whose life could be saved on the other hand, the organ trade should be legalized. Conversely, surveys conducted among living donors postoperatively and in a period of five years following the procedure have shown extreme regret in a majority of the donors, who said that given the chance to repeat the procedure, they would not. Additionally, many study participants reported a decided worsening of economic condition following the procedure. These studies looked only at people who sold a kidney in countries where organ sales are already legal. A consequence of the black market for organs has been a number of cases and suspected cases of organ theft, including murder for the purposes of organ theft. Proponents of a legal market for organs say that the black-market nature of the current trade allows such tragedies and that regulation of the market could prevent them. Opponents say that such a market would encourage criminals by making it easier for them to claim that their stolen organs were legal. Legalization of the organ trade carries with it its own sense of justice as well. Continuing black-market trade creates further disparity on the demand side: only the rich can afford such organs. Legalization of the international organ trade could lead to increased supply, lowering prices so that persons outside the wealthiest segments could afford such organs as well. Exploitation arguments generally come from two main areas: Physical exploitation suggests that the operations in question are quite risky, and, taking place in third-world hospitals or "back-alleys", even more risky. Yet, if the operations in question can be made safe, there is little threat to the donor. Financial exploitation suggests that the donor (especially in the Indian subcontinent and Africa) are not paid enough. Commonly, accounts from persons who have sold organs in both legal and black market circumstances put the prices at between $150 and $5,000, depending on the local laws, supply of ready donors and scope of the transplant operation. In Chennai, India, where one of the largest black markets for organs is known to exist, studies have placed the average sale price at little over $1,000. Many accounts also exist of donors being postoperatively denied their promised pay.The New Cannibalism is a phrase coined by anthropologist Nancy Scheper-Hughes in 1998 for an article written for The New Internationalist. Her argument was that the actual exploitation is an ethical failing, a human exploitation; a perception of the poor as organ sources which may be used to extend the lives of the wealthy.Economic drivers leading to increased donation are not limited to areas such as India and Africa, but also are emerging in the United States. Increasing funeral expenses combined with decreasing real value of investments such as homes and retirement savings which took place in the 2000s have purportedly led to an increase in citizens taking advantage of arrangements where funeral costs are reduced or eliminated. Brain death versus cardiac death Brain death may result in legal death, but still with the heart beating and with mechanical ventilation, keeping all other vital organs alive and functional for a certain period of time. Given long enough, patients who do not fully die in the complete biological sense, but who are declared brain dead, will usually start to build up toxins and wastes in the body. In this way, the organs can eventually dysfunction due to coagulopathy, fluid or electrolyte and nutrient imbalances, or even fail. Thus, the organs will usually only be sustainable and viable for acceptable use up until a certain length of time. This may depend on factors such as how well the patient is maintained, any comorbidities, the skill of the healthcare teams and the quality their facilities. A major point of contention is whether transplantation should be allowed at all if the patient is not yet fully biologically dead, and if brain death is acceptable, whether the persons whole brain needs to have died, or if the death of a certain part of the brain is enough for legal and ethical and moral purposes. Most organ donation for organ transplantation is done in the setting of brain death. However, in Japan this is a fraught point, and prospective donors may designate either brain death or cardiac death – see organ transplantation in Japan. In some nations such as Belgium, France, Netherlands, New Zealand, Poland, Portugal, Singapore and Spain, everyone is automatically an organ donor unless they opt out of the system. Elsewhere, consent from family members or next-of-kin is required for organ donation. The non-living donor is kept on ventilator support until the organs have been surgically removed. If a brain-dead individual is not an organ donor, ventilator and drug support is discontinued and cardiac death is allowed to occur. In the United States, where since the 1980s the Uniform Determination of Death Act has defined death as the irreversible cessation of the function of either the brain or the heart and lungs, the 21st century has seen an order-of-magnitude increase of donation following cardiac death. In 1995, only one out of 100 dead donors in the nation gave their organs following the declaration of cardiac death. That figure grew to almost 11 percent in 2008, according to the Scientific Registry of Transplant Recipients. That increase has provoked ethical concerns about the interpretation of "irreversible" since "patients may still be alive five or even 10 minutes after cardiac arrest because, theoretically, their hearts could be restarted, [and thus are] clearly not dead because their condition was reversible." Gender inequality The majority of organ donors are women. For example, in the United States, 62% of kidney donors and 53% of liver donors are women. In India, women constitute 74% of kidney donors and 60.5% of liver donors. Additionally, the number of female organ recipients is conspicuously lower than that of male recipients. In the U.S., 35% of liver recipients and 39% of kidney recipients are women. In India, the figures are 24% and 19% respectively. Political issues There are also controversial issues regarding how organs are allocated to recipients. For example, some believe that livers should not be given to alcoholics in danger of reversion, while others view alcoholism as a medical condition like diabetes. Faith in the medical system is important to the success of organ donation. Brazil switched to an opt-out system and ultimately had to withdraw it because it further alienated patients who already distrusted the countrys medical system. Adequate funding, strong political will to see transplant outcomes improve, and the existence of specialized training, care and facilities also increase donation rates. Expansive legal definitions of death, such as Spain uses, also increase the pool of eligible donors by allowing physicians to declare a patient to be dead at an earlier stage, when the organs are still in good physical condition. Allowing or forbidding payment for organs affects the availability of organs. Generally, where organs cannot be bought or sold, quality and safety are high, but supply is not adequate to the demand. Where organs can be purchased, the supply increases. Iran adopted a system of paying kidney donors in 1988 and within 11 years it became the only country in the world to clear its waiting list for transplants. Healthy humans have two kidneys, a redundancy that enables living donors (inter vivos) to give a kidney to someone who needs it. The most common transplants are to close relatives, but people have given kidneys to other friends. The rarest type of donation is the undirected donation whereby a donor gives a kidney to a stranger. Less than a few hundred of such kidney donations have been performed. In recent years, searching for altruistic donors via the internet has also become a way to find life saving organs. However, internet advertising for organs is a highly controversial practice, as some scholars believe it undermines the traditional list-based allocation system.The National Transplant Organization of Spain is one of the most successful in the world (Spain has been the world leader in organ donation for decades), but it still cannot meet the demand, as 10% of those needing a transplant die while still on the transplant list. Donations from corpses are anonymous, and a network for communication and transport allows fast extraction and transplant across the country. Under Spanish law, every corpse can provide organs unless the deceased person had expressly rejected it. Because family members still can forbid the donation, carefully trained doctors ask the family for permission, making it very similar in practice to the United States system.In the overwhelming majority of cases, organ donation is not possible for reasons of recipient safety, match failures, or organ condition. Even in Spain, which has the highest organ donation rate in the world, there are only 35.1 actual donors per million people, and there are hundreds of patients on the waiting list. This rate compares to 24.8 per million in Austria, where families are rarely asked to donate organs, and 22.2 per million in France, which—like Spain—has a presumed-consent system. Prison inmates In the United States, prisoners are not discriminated against as organ recipients and are equally eligible for organ transplants along with the general population. A 1976 U.S. Supreme Court case ruled that withholding health care from prisoners constituted "cruel and unusual punishment". United Network for Organ Sharing, the organization that coordinates available organs with recipients, does not factor a patients prison status when determining suitability for a transplant. An organ transplant and follow-up care can cost the prison system up to one million dollars. If a prisoner qualifies, a state may allow compassionate early release to avoid high costs associated with organ transplants. However, an organ transplant may save the prison system substantial costs associated with dialysis and other life-extending treatments required by the prisoner with the failing organ. For example, the estimated cost of a kidney transplant is about $111,000. A prisoners dialysis treatments are estimated to cost a prison $120,000 per year.Because donor organs are in short supply, there are more people waiting for a transplant than available organs. When a prisoner receives an organ, there is a high probability that someone else will die waiting for the next available organ. A response to this ethical dilemma states that felons who have a history of violent crime, who have violated others basic rights, have lost the right to receive an organ transplant, though it is noted that it would be necessary "to reform our justice system to minimize the chance of an innocent person being wrongly convicted of a violent crime and thus being denied an organ transplant".Prisons typically do not allow inmates to donate organs to anyone but immediate family members. There is no law against prisoner organ donation; however, the transplant community has discouraged use of prisoners organs since the early 1990s due to concern over prisons high-risk environment for infectious diseases. Physicians and ethicists also criticize the idea because a prisoner is not able to consent to the procedure in a free and non-coercive environment, especially if given inducements to participate. However, with modern testing advances to more safely rule out infectious disease and by ensuring that there are no incentives offered to participate, some have argued that prisoners can now voluntarily consent to organ donation just as they can now consent to medical procedures in general. With careful safeguards, and with over 2 million prisoners in the U.S., they reason that prisoners can provide a solution for reducing organ shortages in the U.S.While some have argued that prisoner participation would likely be too low to make a difference, one Arizona program started by former Maricopa County Sheriff Joe Arpaio encourages inmates to voluntarily sign up to donate their heart and other organs. As of 2015, there have been over 16,500 participants. Similar initiatives have been started in other US states. In 2013, Utah became the first state to allow prisoners to sign up for organ donation upon death. Religious viewpoints There are several different religions that have different perspectives. Islam has a conflicting view regarding the issue, with half believing that it is against the religion. Muslims are commanded to seek medical attention when in need and saving life is a very important factor of the Islamic religion. Christianity is lenient on the topic of organ donation, and believe it is a service of life.All major religions accept organ donation in at least some form on either utilitarian grounds (i.e., because of its life-saving capabilities) or deontological grounds (e.g., the right of an individual believer to make his or her own decision). Most religions, among them the Roman Catholic Church, support organ donation on the grounds that it constitutes an act of charity and provides a means of saving a life. One religious group, The Jesus Christians, became known as "The Kidney Cult" because more than half its members had donated their kidneys altruistically. Jesus Christians claim altruistic kidney donation is a great way to "Do unto others what they would want you to do unto them." Some religions impose certain restrictions on the types of organs that may be donated and/or on the means by which organs may be harvested and/or transplanted. For example, Jehovahs Witnesses require that organs be drained of any blood due to their interpretation of the Hebrew Bible/Christian Old Testament as prohibiting blood transfusion, and Muslims require that the donor have provided written consent in advance. A few groups disfavor organ transplantation or donation; notably, these include Shinto and the Romani.Orthodox Judaism considers organ donation obligatory if it will save a life, as long as the donor is considered dead as defined by Jewish law. In both Orthodox Judaism and non-Orthodox Judaism, the majority view holds that organ donation is permitted in the case of irreversible cardiac rhythm cessation. In some cases, rabbinic authorities believe that organ donation may be mandatory, whereas a minority opinion considers any donation of a live organ as forbidden. Organ shortfall The demand for organs significantly surpasses the number of donors everywhere in the world. There are more potential recipients on organ donation waiting lists than organ donors. In particular, due to significant advances in dialysis techniques, patients with end-stage renal disease (ESRD) can survive longer than ever before. Because these patients do not die as quickly as they used to, and as kidney failure increases with the rising age and prevalence of high blood pressure and diabetes in a society, the need especially for kidneys rises every year.As of March 2014, about 121,600 people in the United States are on the waiting list, although about a third of those patients are inactive and could not receive a donated organ. Wait times and success rates for organs differ significantly between organs due to demand and procedure difficulty. As of 2007, three-quarters of patients in need of an organ transplant were waiting for a kidney, and as such kidneys have much longer waiting times. As stated by the Gift of Life Donor Program website, the median patient who ultimately received an organ waited 4 months for a heart or lung—but 18 months for a kidney, and 18–24 months for a pancreas because demand for these organs substantially outstrips supply. An increased prevalence of self-driving cars could exacerbate this problem: In the US, 13% of organ donations come from car crash victims, and autonomous vehicles are projected to reduce the frequency of car crashes.In Australia, there are 10.8 transplants per million people, about a third of the Spanish rate. The Lions Eye Institute, in Western Australia, houses the Lions Eye Bank. The Bank was established in 1986 and coordinates the collection, processing and distribution of eye tissue for transplantation. The Lions Eye Bank also maintains a waitlist of patients who require corneal graft operations. About 100 corneas are provided by the Bank for transplant each year, but there is still a waiting list for corneas. "To an economist, this is a basic supply-and-demand gap with tragic consequences." Approaches to addressing this shortfall include: Donor registries and "primary consent" laws, to remove the burden of the donation decision from the legal next-of-kin. Illinois adopted a policy of "mandated choice"

Organ donation

in 2006, which requires drivers license registrants to answer the question "Do you want to be an organ donor?" Illinois has a registration rate of 60 percent compared to 38 percent nationally. The added cost of adding a question to the registration form is minimal. Monetary incentives for signing up to be a donor. Some economists have advocated going as far as allowing the sale of organs. The New York Times reported that "Gary Becker and Julio Jorge Elias argued in a recent paper that monetary incentives would increase the supply of organs for transplant sufficiently to eliminate the very large queues in organ markets, and the suffering and deaths of many of those waiting, without increasing the total cost of transplant surgery by more than 12 percent." Iran allows the sale of kidneys and has no waiting list. Organ futures have been proposed to incentivise donation through direct or indirect compensation. The primary argument against such proposals is a moral one; as the article notes, many find such a suggestion repugnant. As the National Kidney Foundation puts it, "Offering direct or indirect economic benefits in exchange for organ donation is inconsistent with our values as a society. Any attempt to assign a monetary value to the human body, or body parts, either arbitrarily, or through market forces, diminishes human dignity." An opt-out system ("dissent solution"), in which a potential donor or his/her relatives must take specific action to be excluded from organ donation, rather than specific action to be included. This model is used in several European countries, such as Austria, which has a registration rate eight times that of Germany, which uses an opt-in system. Social incentive programs, wherein members sign a legal agreement to direct their organs first to other members who are on the transplant waiting list. One historical example of a private organization using this model is LifeSharers, which is free to join and whose members agree to sign a document giving preferred access to their organs. "The proposal [for an organ mutual insurance pool] can be easily summarized: An individual would receive priority for any needed transplant if that individual agrees that his or her organs will be available to other members of the insurance pool in the event of his or her death. … The main purpose [of this proposal] is to increase the supply of transplantable organs in order to save or improve more lives." Technical advances allows the use of donors that were previously rejected. For example, hepatitis C can be knowingly transplanted and treated in the organ recipient.In hospitals, organ network representatives routinely screen patient records to identify potential donors shortly in advance of their deaths. In many cases, organ-procurement representatives will request screening tests (such as blood typing) or organ-preserving drugs (such as blood pressure drugs) to keep potential donors organs viable until their suitability for transplants can be determined and family consent (if needed) can be obtained. This practice increases transplant efficiency, as potential donors who are unsuitable due to infection or other causes are removed from consideration before their deaths, and decreases the avoidable loss of organs. It may also benefit families indirectly, as the families of unsuitable donors are not approached to discuss organ donation. Distribution The United States has two agencies that govern organ procurement and distribution within the country. The United Network for Organ Sharing and the Organ Procurement and Transplant Network (OPTN) regulate Organ Procurement Organizations (OPO) with regard to procurement and distribution ethics and standards. OPOs are non-profit organizations charged with the evaluation, procurement and allocation of organs within their Designated Service Area (DSA). Once a donor has been evaluated and consent obtained, provisional allocation of organs commences. UNOS developed a computer program that automatically generates donor specific match lists for suitable recipients based on the criteria that the patient was listed with. OPO coordinators enter donor information into the program and run the respective lists. Organ offers to potential recipients are made to transplant centers to make them aware of a potential organ. The surgeon will evaluate the donor information and make a provisional determination of medical suitability to their recipient. Distribution varies slightly between different organs but is essentially very similar. When lists are generated many factors are taken into consideration; these factors include: distance of transplant center from the donor hospital, blood type, medical urgency, wait time, donor size and tissue typing. For heart recipients medical urgency is denoted by a recipients "Status" (Status 1A, 1B and status 2). Lungs are allocated based on a recipients Lung Allocation Score (LAS) that is determined based on the urgency of clinical need as well as the likelihood of benefit from the transplant. Livers are allocated using both a status system and MELD/PELD score (Model for End-stage Liver Disease/Pediatric End-stage Liver Disease). Kidney and pancreas lists are based on location, blood type, Human Leukocyte Antigen (HLA) typing and wait time. When a recipient for a kidney or pancreas has no direct antibodies to the donor HLA the match is said to be a 0 ABDR mismatch or zero antigen mismatch. A zero mismatch organ has a low rate of rejection and allows a recipient to be on lower doses of immunosuppressive drugs. Since zero mismatches have such high graft survival these recipients are afforded priority regardless of location and wait time. UNOS has in place a "Payback" system to balance organs that are sent out of a DSA because of a zero mismatch. Location of a transplant center with respect to a donor hospital is given priority due to the effects of Cold Ischemic Time (CIT). Once the organ is removed from the donor, blood no longer perfuses through the vessels and begins to starve the cells of oxygen (ischemia). Each organ tolerates different ischemic times. Hearts and lungs need to be transplanted within 4–6 hours from recovery, liver about 8–10 hours and pancreas about 15 hours; kidneys are the most resilient to ischemia. Kidneys packaged on ice can be successfully transplanted 24–36 hours after recovery. Developments in kidney preservation have yielded a device that pumps cold preservation solution through the kidneys vessels to prevent Delayed Graft Function (DGF) due to ischemia. Perfusion devices, often called kidney pumps, can extend graft survival to 36–48 hours post recovery for kidneys. Recently similar devices have been developed for the heart and lungs, in an effort to increase distances procurement teams may travel to recover an organ. Suicide People committing suicide have a higher rate of donating organs than average. One reason is lower negative response or refusal rate by the family and relatives, but the explanation for this remains to be clarified. In addition, donation consent is higher than average from people committing suicide.Attempted suicide is a common cause of brain death (3.8%), mainly among young men. Organ donation is more common in this group compared to other causes of death. Brain death may result in legal death, but still with the heart beating, and with mechanical ventilation all other vital organs may be kept completely alive and functional, providing optimal opportunities for organ transplantation. Controversies In 2008, California transplant surgeon Hootan Roozrokh was charged with dependent adult abuse for prescribing what prosecutors alleged were excessive doses of morphine and sedatives to hasten the death of a man with adrenal leukodystrophy and irreversible brain damage, in order to procure his organs for transplant. The case brought against Roozrokh was the first criminal case against a transplant surgeon in the US, and resulted in his acquittal. Further, Dr. Roozrokh successfully sued for defamation stemming from the incident.At Californias Emanuel Medical Center, neurologist Narges Pazouki, MD, said an organ-procurement organization representative pressed her to declare a patient brain-dead before the appropriate tests had been done. In September 1999, eBay blocked an auction for "one functional human kidney" which had reached a highest bid of $5.7 million. Under United States federal laws, eBay was obligated to dismiss the auction for the selling of human organs which is punishable by up to five years in prison and a $50,000 fine.On June 27, 2008, Indonesian Sulaiman Damanik, 26, pled guilty in a Singapore court for sale of his kidney to CK Tangs executive chair, Mr. Tang Wee Sung, 55, for 150 million rupiah (US$17,000). The Transplant Ethics Committee must approve living donor kidney transplants. Organ trading is banned in Singapore and in many other countries to prevent the exploitation of "poor and socially disadvantaged donors who are unable to make informed choices and suffer potential medical risks." Toni, 27, the other accused, donated a kidney to an Indonesian patient in March, alleging he was the patients adopted son, and was paid 186 million rupiah (US$21,000). Public service announcements Marketing for organ donation must walk a fine line between stressing the need for organ donation and not being too forceful. If the marketing agent is too forceful, then the target of the message will react defensively to the request. According to psychological reactance theory, a person will perceive their freedom threatened and will react to restore the freedom. According to Ashley Anker, the use of transportation theory has a positive effect on target reactions by marketing attempts. When public service announcements use recipient-focused messages, targets were more transported. Individuals who watched recipient-focused messages were more transported because potential donors experience empathy for the potential recipient. Future public service announcements should use recipient-focused stories to elicit relationship formation between potential donors and recipients. Awareness about organ donation leads to greater social support for organ donation, in turn leading to greater registration. By starting with promoting college students awareness of organ donation and moving to increasing social support for organ donation, the more likely people will be to register as organ donors.The United States Department of Health funded a study by the University of Wisconsin Hospital to increase efforts to increase awareness and the number of registered donors by pursuing members of the university and their family and friends through social media. The results of the study showed a 20% increase in organ donation by creating support and awareness through social media. See also References External links National Institute of Healths MedLine on Organ Donation Organ Donation India NHS Organ Transplant (UK) OrganDonor.gov (US) Portal for Organ Donation After Execution Portal for The National Network of Organ Donors Human Tissue Donation – NPR News Investigation Organ and Tissue Donation What Every Nurse Needs to Know course on www.RN.org

Combined immunodeficiencies

Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both humoral immunity and cell-mediated immunity. This category includes conditions such as bare lymphocyte syndrome, as well as severe combined immunodeficiency. Combined immunodeficiencies are commonly distinguished from SCID by low but not absent T-cell function.ICD-9 divides immune deficiencies into three categories: humoral (279.0), cell-mediated (279.1), and combined (279.2). However, ICD-10 does not include a category for cell-mediated immune dysfunction (antibody is D80, and combined is D81), thus grouping T-cell mediated conditions with combined conditions. References == External links ==

Oligomenorrhea

Oligomenorrhea is infrequent (or, in occasional usage, very light) menstruation. More strictly, it is menstrual periods occurring at intervals of greater than 35 days, with only four to nine periods in a year. Menstrual periods should have been regularly established before the development of infrequent flow. The duration of such events may vary. Causes Oligomenorrhea can be a result of prolactinomas (adenomas of the anterior pituitary). It may be caused by thyrotoxicosis, hormonal changes in perimenopause, Prader–Willi syndrome, and Graves disease. Endurance exercises such as running or swimming can affect the reproductive physiology of female athletes. Female runners, swimmers and ballet dancers either menstruate infrequently in comparison to non-athletic females of comparable age or exhibit amenorrhea. A more recent study shows that athletes competing in sports that emphasise thinness or a specific weight exhibit a higher rate of menstrual dysfunction than either athletes competing in sports with less focus on these or control subjects.Breastfeeding has been linked to irregularity of menstrual cycles due to hormones that delay ovulation. People with polycystic ovary syndrome (PCOS) are also likely to have oligomenorrhea. PCOS is a condition in which excessive androgens (male sex hormones) are released by the ovaries. People with PCOS show menstrual irregularities that range from oligomenorrhea and amenorrhea, to very heavy, irregular periods. The condition affects about 6% of premenopausal females. Eating disorders can result in oligomenorrhea. Although menstrual disorders are most strongly associated with anorexia nervosa, bulimia nervosa may also result in oligomenorrhea or amenorrhea. There is some controversy regarding the mechanism for the menstrual dysregulation, since amenorrhea may sometimes precede substantial weight loss in some anorexics. See also Amenorrhea: a total cessation of the menstrual period Menorrhagia: unusually heavy periods References == External links ==

Allergic rhinitis

Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and watery eyes, and swelling around the eyes. The fluid from the nose is usually clear. Symptom onset is often within minutes following allergen exposure, and can affect sleep and the ability to work or study. Some people may develop symptoms only during specific times of the year, often as a result of pollen exposure. Many people with allergic rhinitis also have asthma, allergic conjunctivitis, or atopic dermatitis.Allergic rhinitis is typically triggered by environmental allergens such as pollen, pet hair, dust, or mold. Inherited genetics and environmental exposures contribute to the development of allergies. Growing up on a farm and having multiple siblings decreases this risk. The underlying mechanism involves IgE antibodies that attach to an allergen, and subsequently result in the release of inflammatory chemicals such as histamine from mast cells. It causes mucous membranes in the nose, eyes and throat to become inflamed and itchy as they work to eject the allergen. Diagnosis is typically based on a combination of symptoms and a skin prick test or blood tests for allergen-specific IgE antibodies. These tests, however, can be falsely positive. The symptoms of allergies resemble those of the common cold; however, they often last for more than two weeks and, despite the common name, typically do not include a fever.Exposure to animals early in life might reduce the risk of developing these specific allergies. Several different types of medications reduce allergic symptoms, including nasal steroids, antihistamines, such as diphenhydramine, cromolyn sodium, and leukotriene receptor antagonists such as montelukast. Oftentimes, medications do not completely control symptoms, and they may also have side effects. Exposing people to larger and larger amounts of allergen, known as allergen immunotherapy (AIT), is often effective. The allergen can be given as an injection under the skin or as a tablet under the tongue. Treatment typically lasts three to five years, after which benefits may be prolonged.Allergic rhinitis is the type of allergy that affects the greatest number of people. In Western countries, between 10 and 30% of people are affected in a given year. It is most common between the ages of twenty and forty. The first accurate description is from the 10th-century physician Abu Bakr al-Razi. In 1859, Charles Blackley identified pollen as the cause. In 1906, the mechanism was determined by Clemens von Pirquet. The link with hay came about due to an early (and incorrect) theory that the symptoms were brought about by the smell of new hay. Although the scent per se is irrelevant, the correlation with hay remains more than random, as peak hay-harvesting season overlaps with peak pollen season, and hay-harvesting work puts people in close contact with seasonal allergens. Signs and symptoms The characteristic symptoms of allergic rhinitis are: rhinorrhea (excess nasal secretion), itching, sneezing fits, and nasal congestion and obstruction. Characteristic physical findings include conjunctival swelling and erythema, eyelid swelling with Dennie–Morgan folds, lower eyelid venous stasis (rings under the eyes known as "allergic shiners"), swollen nasal turbinates, and middle ear effusion.There can also be behavioral signs; in order to relieve the irritation or flow of mucus, people may wipe or rub their nose with the palm of their hand in an upward motion: an action known as the "nasal salute" or the "allergic salute". This may result in a crease running across the nose (or above each nostril if only one side of the nose is wiped at a time), commonly referred to as the "transverse nasal crease", and can lead to permanent physical deformity if repeated enough.People might also find that cross-reactivity occurs. For example, people allergic to birch pollen may also find that they have an allergic reaction to the skin of apples or potatoes. A clear sign of this is the occurrence of an itchy throat after eating an apple or sneezing when peeling potatoes or apples. This occurs because of similarities in the proteins of the pollen and the food. There are many cross-reacting substances. Hay fever is not a true fever, meaning it does not cause a core body temperature in the fever over 37.5–38.3 °C (99.5–100.9 °F). Cause Pollen is often considered as a cause of allergic rhinitis, hence called hay fever (See sub-section below). Predisposing factors to allergic rhinitis include eczema (atopic dermatitis) and asthma. These three conditions can often occur together which is referred to as the atopic triad. Additionally, environmental exposures such as air pollution and maternal tobacco smoking can increase an individuals chances of developing allergies. Pollen-related causes Allergic rhinitis triggered by the pollens of specific seasonal plants is commonly known as "hay fever", because it is most prevalent during haying season. However, it is possible to have allergic rhinitis throughout the year. The pollen that causes hay fever varies between individuals and from region to region; in general, the tiny, hardly visible pollens of wind-pollinated plants are the predominant cause. Pollens of insect-pollinated plants are too large to remain airborne and pose no risk. Examples of plants commonly responsible for hay fever include: Trees: such as pine (Pinus), mulberry (Morus), birch (Betula), alder (Alnus), cedar (Cedrus), hazel (Corylus), hornbeam (Carpinus), horse chestnut (Aesculus), willow (Salix), poplar (Populus), plane (Platanus), linden/lime (Tilia), and olive (Olea). In northern latitudes, birch is considered to be the most common allergenic tree pollen, with an estimated 15–20% of people with hay fever sensitive to birch pollen grains. A major antigen in these is a protein called Bet V I. Olive pollen is most predominant in Mediterranean regions. Hay fever in Japan is caused primarily by sugi (Cryptomeria japonica) and hinoki (Chamaecyparis obtusa) tree pollen. "Allergy friendly" trees include: female ash, red maple, yellow poplar, dogwood, magnolia, double-flowered cherry, fir, spruce, and flowering plum. Grasses (Family Poaceae): especially ryegrass (Lolium sp.) and timothy (Phleum pratense). An estimated 90% of people with hay fever are allergic to grass pollen. Weeds: ragweed (Ambrosia), plantain (Plantago), nettle/parietaria (Urticaceae), mugwort (Artemisia Vulgaris), Fat hen (Chenopodium), and sorrel/dock (Rumex)Allergic rhinitis may also be caused by allergy to Balsam of Peru, which is in various fragrances and other products. Genetic factors The causes and pathogenesis of allergic rhinitis are hypothesized to be affected by both genetic and environmental factors, with many recent studies focusing on specific loci that could be potential therapeutic targets for the disease. Genome-wide association studies (GWAS) have identified a number of different loci and genetic pathways that seem to mediate the bodys response to allergens and promote the development of allergic rhinitis, with some of the most promising results coming from studies involving single-nucleotide polymorphisms (SNPs) in the interleukin-33 (IL-33) gene. The IL-33 protein that is encoded by the IL-33 gene is part of the interleukin family of cytokines that interact with T-helper 2 (Th2) cells, a specific type of T cell. Th2 cells contribute to the bodys inflammatory response to allergens, and specific ST2 receptors, also known as IL1RL1, on these cells bind to the ligand IL-33 protein. This IL-33/ST2 signaling pathway has been found to be one of the main genetic determinants in bronchial asthma pathogenesis, and because of the pathological linkage between asthma and rhinitis, the experimental focus of IL-33 has now turned to its role in the development of allergic rhinitis in humans and mouse models. Recently, it was found that allergic rhinitis patients expressed higher levels of IL-33 in their nasal epithelium and had a higher concentration of ST2 serum in nasal passageways following their exposure to pollen and other allergens, indicating that this gene and its associated receptor are expressed at a higher rate in allergic rhinitis patients. In a 2020 study on polymorphisms of the IL-33 gene and their link to allergic rhinitis within the Han Chinese population, researchers found that five SNPs specifically contributed to the pathogenesis of allergic rhinitis, with three of those five SNPs previously identified as genetic determinants for asthma.Another study focusing on Han Chinese children found that certain SNPs in the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene can be associated with childhood allergic rhinitis and allergic asthma. The encoded PTPN22 protein, which is found primarily in lymphoid tissue, acts as a post-translational regulator by removing phosphate groups from targeted proteins. Importantly, PTPN22 can affect the phosphorylation of T cell responses, and thus the subsequent proliferation of the T cells. As mentioned earlier, T cells contribute to the bodys inflammatory response in a variety of ways, so any changes to the cells structure and function can have potentially deleterious effects on the bodys inflammatory response to allergens. To date, one SNP in the PTPN22 gene has been found to be significantly associated with allergic rhinitis onset in children. On the other hand, CTLA-4 is an immune-checkpoint protein that helps mediate and control the bodys immune response to prevent overactivation. It is expressed only in T cells as a glycoprotein for the Immunoglobulin (Ig) protein family, also known as antibodies. There have been two SNPs in CTLA-4 that were found to be significantly associated with childhood allergic rhinitis. Both SNPs most likely affect the associated proteins shape and function, causing the body to exhibit an overactive immune response to the posed allergen. The polymorphisms in both genes are only beginning to be examined, therefore more research is needed to determine the severity of the impact of polymorphisms in the respective genes.Finally, epigenetic alterations and associations are of particular interest to the study and ultimate treatment of allergic rhinitis. Specifically, microRNAs (miRNA) are hypothesized to be imperative to the pathogenesis of allergic rhinitis due to the post-transcriptional regulation and repression of translation in their mRNA complement. Both miRNAs and their common carrier vessel exosomes have been found to play a role in the bodys immune and inflammatory responses to allergens. miRNAs are housed and packaged inside of exosomes until they are ready to be released into the section of the cell that they are coded to reside and act. Repressing the translation of proteins can ultimately repress parts of the bodys immune and inflammatory responses, thus contributing to the pathogenesis of allergic rhinitis and other autoimmune disorders. There are many miRNAs that have been deemed potential therapeutic targets for the treatment of allergic rhinitis by many different researchers, with the most widely studied being miR-133, miR-155, miR-205, miR-498, and let-7e. Diagnosis Allergy testing may reveal the specific allergens to which an individual is sensitive. Skin testing is the most common method of allergy testing. This may include a patch test to determine if a particular substance is causing the rhinitis, or an intradermal, scratch, or other test. Less commonly, the suspected allergen is dissolved and dropped onto the lower eyelid as a means of testing for allergies. This test should be done only by a physician, since it can be harmful if done improperly. In some individuals not able to undergo skin testing (as determined by the doctor), the RAST blood test may be helpful in determining specific allergen sensitivity. Peripheral eosinophilia can be seen in differential leukocyte count.Allergy testing is not definitive. At times, these tests can reveal positive results for certain allergens that are not actually causing symptoms, and can also not pick up allergens that do cause an individuals symptoms. The intradermal allergy test is more sensitive than the skin prick test, but is also more often positive in people that do not have symptoms to that allergen.Even if a person has negative skin-prick, intradermal and blood tests for allergies, they may still have allergic rhinitis, from a local allergy in the nose. This is called local allergic rhinitis. Specialized testing is necessary to diagnose local allergic rhinitis. Classification Seasonal allergic rhinitis (hay fever): Caused by seasonal peaks in the airborne load of pollens. Perennial allergic rhinitis (nonseasonal allergic rhinitis; atopic rhinitis): Caused by allergens present throughout the year (e.g., dander).Allergic rhinitis may be seasonal, perennial, or episodic. Seasonal allergic rhinitis occurs in particular during pollen seasons. It does not usually develop until after 6 years of age. Perennial allergic rhinitis occurs throughout the year. This type of allergic rhinitis is commonly seen in younger children.Allergic rhinitis may also be classified as mild-intermittent, moderate-severe intermittent, mild-persistent, and moderate-severe persistent. Intermittent is when the symptoms occur <4 days per week or <4 consecutive weeks. Persistent is when symptoms occur >4 days/week and >4 consecutive weeks. The symptoms are considered mild with normal sleep, no impairment of daily activities, no impairment of work or school, and if symptoms are not troublesome. Severe symptoms result in sleep disturbance, impairment of daily activities, and impairment of school or work. Local allergic rhinitis Local allergic rhinitis is an allergic reaction in the nose to an allergen, without systemic allergies. So skin-prick and blood tests for allergy are negative, but there are IgE antibodies produced in the nose that react to a specific allergen. Intradermal skin testing may also be negative.The symptoms of local allergic rhinitis are the same as the symptoms of allergic rhinitis, including symptoms in the eyes. Just as with allergic rhinitis, people can have either seasonal or perennial local allergic rhinitis. The symptoms of local allergic rhinitis can be mild, moderate, or severe. Local allergic rhinitis is associated with conjunctivitis and asthma.In one study, about 25% of people with rhinitis had local allergic rhinitis. In several studies, over 40% of people having been diagnosed with nonallergic rhinitis were found to actually have local allergic rhinitis. Steroid nasal sprays and oral antihistamines have been found to be effective for local allergic rhinitis.As of 2014, local allergenic rhinitis had mostly been investigated in Europe; in the United States, the nasal provocation testing necessary to diagnose the condition was not widely available.: 617 Prevention Prevention often focuses on avoiding specific allergens that cause an individuals symptoms. These methods include not having pets, not having carpets or upholstered furniture in the home, and keeping the home dry. Specific anti-allergy zippered covers on household items like pillows and mattresses have also proven to be effective in preventing dust mite allergies.Studies have shown that growing up on a farm and having many older siblings can decrease an individuals risk for developing allergic rhinitis.Studies in young children have shown that there is higher risk of allergic rhinitis in those who have early exposure to foods or formula or heavy exposure to cigarette smoking within the first year of life. Treatment The goal of rhinitis treatment is to prevent or reduce the symptoms caused by the inflammation of affected tissues. Measures that are effective include avoiding the allergen. Intranasal corticosteroids are the preferred medical treatment for persistent symptoms, with other options if this is not effective. Second line therapies include antihistamines, decongestants, cromolyn, leukotriene receptor antagonists, and nasal irrigation. Antihistamines by mouth are suitable for occasional use with mild intermittent symptoms. Mite-proof covers, air filters, and withholding certain foods in childhood do not have evidence supporting their effectiveness. Antihistamines Antihistamine drugs can be taken orally and nasally to control symptoms such as sneezing, rhinorrhea, itching, and conjunctivitis.It is best to take oral antihistamine medication before exposure, especially for seasonal allergic rhinitis. In the case of nasal antihistamines like azelastine antihistamine nasal spray, relief from symptoms is experienced within 15 minutes allowing for a more immediate as-needed approach to dosage. There is not enough evidence of antihistamine efficacy as an add-on therapy with nasal steroids in the management of intermittent or persistent allergic rhinitis in children, so its adverse effects and additional costs must be considered.Ophthalmic antihistamines (such as azelastine in eye drop form and ketotifen) are used for conjunctivitis, while intranasal forms are used mainly for sneezing, rhinorrhea, and nasal pruritus.Antihistamine drugs can have undesirable side-effects, the most notable one being drowsiness in the case of oral antihistamine tablets. First-generation antihistamine drugs such as diphenhydramine cause drowsiness, while second- and third-generation antihistamines such as cetirizine and loratadine are less likely to.Pseudoephedrine is also indicated for vasomotor rhinitis. It is used only when nasal congestion is present and can be used with antihistamines. In the United States, oral decongestants containing pseudoephedrine must be purchased behind the pharmacy counter in an effort to prevent the manufacturing of methamphetamine. Desloratadine/pseudoephedrine can also be used for this condition Steroids Intranasal corticosteroids are used to control symptoms associated with sneezing, rhinorrhea, itching, and nasal congestion. Steroid nasal sprays are effective and safe, and may be effective without oral antihistamines. They take several days to act and so must be taken continually for several weeks, as their therapeutic effect builds up with time.In 2013, a study compared the efficacy of mometasone furoate nasal spray to betamethasone oral tablets for the treatment of people with seasonal allergic rhinitis and found that the two have virtually equivalent effects on nasal symptoms in people.Systemic steroids such as prednisone tablets and intramuscular triamcinolone acetonide or glucocorticoid (such as betamethasone) injection are effective at reducing nasal inflammation, but their use is limited by their short duration of effect and the side-effects of prolonged steroid therapy. Other Other measures that may be used second line include: decongestants, cromolyn, leukotriene receptor antagonists, and nonpharmacologic therapies such as nasal irrigation.Topical decongestants may also be helpful in reducing symptoms such as nasal congestion, but should not be used for long periods, as stopping them after protracted use can lead to a rebound nasal congestion called rhinitis medicamentosa.For nocturnal symptoms, intranasal corticosteroids can be combined with nightly oxymetazoline, an adrenergic alpha-agonist, or an antihistamine nasal spray without risk of rhinitis medicamentosa.Nasal saline irrigation (a practice where salt water is poured into the nostrils), may have benefits in both adults and children in relieving the symptoms of allergic rhinitis and it is unlikely to be associated with adverse effects. Allergen immunotherapy Allergen immunotherapy (AIT, also termed desensitization) treatment involves administering doses of allergens to accustom the body to substances that are generally harmless (pollen, house dust mites), thereby inducing specific long-term tolerance. Allergen immunotherapy is the only treatment that alters the disease mechanism. Immunotherapy can be administered orally (as sublingual tablets or sublingual drops), or by injections under the skin (subcutaneous). Subcutaneous immunotherapy is the most common form and has the largest body of evidence supporting its effectiveness. Alternative medicine There are no forms of complementary or alternative medicine that are evidence-based for allergic rhinitis. Therapeutic efficacy of alternative treatments such as acupuncture and homeopathy is not supported by available evidence. While some evidence shows that acupuncture is effective for rhinitis, specifically targeting the sphenopalatine ganglion acupoint, these trials are still limited. Overall, the quality of evidence for complementary-alternative medicine is not strong enough to be recommended by the American Academy of Allergy, Asthma and Immunology. Epidemiology Allergic rhinitis is the type of allergy that affects the greatest number of people. In Western countries, between 10 and 30 percent of people are affected in a given year. It is most common between the ages of twenty and forty. History The first accurate description is from the 10th century physician Rhazes. Pollen was identified as the cause in 1859 by Charles Blackley. In 1906 the mechanism was determined by Clemens von Pirquet. The link with hay came about due to an early (and incorrect) theory that the symptoms were brought about by the smell of new hay. References Further reading External links Allergic rhinitis at Curlie Types of Pollen Allergies

Organ (biology)

In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a function. Tissues of different types combine to form an organ which has a specific function. The intestinal wall for example is formed by epithelial tissue and smooth muscle tissue. Two or more organs working together in the execution of a specific body function form an organ system, also called a biological system or body system. An organs tissues can be broadly categorized as parenchyma, the functional tissue, and stroma, the structural tissue with supportive, connective, or ancillary functions. For example, the glands tissue that makes the hormones is the parenchyma, whereas the stroma includes the nerves that innervate the parenchyma, the blood vessels that oxygenate and nourish it and carry away its metabolic wastes, and the connective tissues that provide a suitable place for it to be situated and anchored. The main tissues that make up an organ tend to have common embryologic origins, such as arising from the same germ layer. Organs exist in most multicellular organisms. In single-celled organisms such as bacteria, the functional analogue of an organ is known as an organelle. In plants, there are three main organs.In the study of anatomy, viscera (singular viscus) refers to the internal organs of the abdominal, thoracic, and pelvic cavities. The abdominal organs may be classified as solid organs, or hollow organs. The solid organs are the liver, pancreas, spleen, kidneys, and adrenal glands. The hollow organs of the abdomen are the stomach, intestines, gallbladder, bladder, and rectum. In the thoracic cavity the heart is a hollow, muscular organ.The number of organs in any organism depends on the definition used. By one widely adopted definition, 79 organs have been identified in the human body. Animals Except for placozoans, multicellular animals including humans have a variety of organ systems. These specific systems are widely studied in human anatomy. The functions of these organ systems often share significant overlap. For instance, the nervous and endocrine system both operate via a shared organ, the hypothalamus. For this reason, the two systems are combined and studied as the neuroendocrine system. The same is true for the musculoskeletal system because of the relationship between the muscular and skeletal systems. Cardiovascular system: pumping and channeling blood to and from the body and lungs with heart, blood and blood vessels. Digestive system: digestion and processing food with salivary glands, esophagus, stomach, liver, gallbladder, pancreas, intestines, colon, rectum and anus. Endocrine system: communication within the body using hormones made by endocrine glands such as the hypothalamus, pituitary gland, pineal body or pineal gland, thyroid, parathyroids and adrenals, i.e., adrenal glands. Excretory system: kidneys, ureters, bladder and urethra involved in fluid balance, electrolyte balance and excretion of urine. Lymphatic system: structures involved in the transfer of lymph between tissues and the blood stream, the lymph and the nodes and vessels that transport it including the immune system: defending against disease-causing agents with leukocytes, tonsils, adenoids, thymus and spleen. Integumentary system: skin, hair and nails of mammals. Also scales of fish, reptiles, and birds, and feathers of birds. Muscular system: movement with muscles. Nervous system: collecting, transferring and processing information with brain, spinal cord and nerves. Reproductive system: the sex organs, such as ovaries, fallopian tubes, uterus, vulva, vagina, testes, vas deferens, seminal vesicles, prostate and penis. Respiratory system: the organs used for breathing, the pharynx, larynx, trachea, bronchi, lungs and diaphragm. Skeletal system: structural support and protection with bones, cartilage, ligaments and tendons. Viscera In the study of anatomy, viscera (singular viscus) refers to the internal organs of the abdominal, thoracic, and pelvic cavities. The abdominal organs may be classed as solid organs, or hollow organs. The solid organs are the liver, pancreas, spleen, kidneys, and adrenal glands. The hollow organs are the stomach, intestines, gallbladder, bladder, and rectum. In the thoracic cavity the heart is a hollow, muscular organ. Splanchnology is the study of the viscera. The term "visceral" is contrasted with the term "parietal", meaning "of or relating to the wall of a body part, organ or cavity" The two terms are often used in describing a membrane or piece of connective tissue, referring to the opposing sides. Origin and evolution The organ level of organisation in animals can be first detected in flatworms and the more derived phyla, i.e. the bilaterians. The less-advanced taxa (i.e. Placozoa, Porifera, Ctenophora and Cnidaria) do not show consolidation of their tissues into organs. More complex animals are composed of different organs, which have evolved over time. For example, the liver and heart evolved in the chordates about 550-500 million years ago, while the gut and brain are even more ancient, arising in the ancestor of vertebrates, insects, molluscs, and worms about 700-650 million years ago. Given the ancient origin of most vertebrate organs, researchers have looked for model systems, where organs have evolved more recently, and ideally have evolved multiple times independently. An outstanding model for this kind of research is the placenta, which has evolved more than 100 times independently in vertebrates, has evolved relatively recently in some lineages, and exists in intermediate forms in extant taxa. Studies on the evolution of the placenta have identified a variety of genetic and physiological processes that contribute to the origin and evolution of organs, these include the re-purposing of existing animal tissues, the acquisition of new functional properties by these tissues, and novel interactions of distinct tissue types. Plants The study of plant organs is covered in plant morphology. Organs of plants can be divided into vegetative and reproductive. Vegetative plant organs include roots, stems, and leaves. The reproductive organs are variable. In flowering plants, they are represented by the flower, seed and fruit. In conifers, the organ that bears the reproductive structures is called a cone. In other divisions (phyla) of plants, the reproductive organs are called strobili, in Lycopodiophyta, or simply gametophores in mosses. Common organ system designations in plants include the differentiation of shoot and root. All parts of the plant above ground (in non-epiphytes), including the functionally distinct leaf and flower organs, may be classified together as the shoot organ system.The vegetative organs are essential for maintaining the life of a plant. While there can be 11 organ systems in animals, there are far fewer in plants, where some perform the vital functions, such as photosynthesis, while the reproductive organs are essential in reproduction. However, if there is asexual vegetative reproduction, the vegetative organs are those that create the new generation of plants (see clonal colony). Society and culture Many societies have a system for organ donation, in which a living or deceased donors organ are transplanted into a person with a failing organ. The transplantation of larger solid organs often requires immunosuppression to prevent organ rejection or graft-versus-host disease. There is considerable interest throughout the world in creating laboratory-grown or artificial organs. Organ transplants Beginning in the 20th century organ transplants began to take place as scientists knew more about the anatomy of organs. These came later in time as procedures were often dangerous and difficult. Both the source and method of obtaining the organ to transplant are major ethical issues to consider, and because organs as resources for transplant are always more limited than demand for them, various notions of justice, including distributive justice, are developed in the ethical analysis. This situation continues as long as transplantation relies upon organ donors rather than technological innovation, testing, and industrial manufacturing. History The English word "organ" dates back to the twelfth century and refers to any musical instrument. By the late 14th century, the musical terms meaning had narrowed to refer specifically to the keyboard-based instrument. At the same time, a second meaning arose, in reference to a "body part adapted to a certain function".Plant organs are made from tissue composed of different types of tissue. The three tissue types are ground, vascular, and dermal. When three or more organs are present, it is called an organ system.The adjective visceral, also splanchnic, is used for anything pertaining to the internal organs. Historically, viscera of animals were examined by Roman pagan priests like the haruspices or the augurs in order to divine the future by their shape, dimensions or other factors. This practice remains an important ritual in some remote, tribal societies. The term "visceral" is contrasted with the term "parietal", meaning "of or relating to the wall of a body part, organ or cavity" The two terms are often used in describing a membrane or piece of connective tissue, referring to the opposing sides. Antiquity Aristotle used the word frequently in his philosophy, both to describe the organs of plants or animals (e.g. the roots of a tree, the heart or liver of an animal), and to describe more abstract "parts" of an interconnected whole (e.g. his logical works, taken as a whole, are referred to as the Organon).Some alchemists (e.g. Paracelsus) adopted the Hermetic Qabalah assignment between the seven vital organs and the seven classical planets as follows: See also Organoid Organ-on-a-chip References External links Media related to Organs (anatomy) at Wikimedia Commons

Self-esteem

Self-esteem is confidence in ones own worth or abilities. Self-esteem encompasses beliefs about oneself (for example, "I am loved", "I am worthy") as well as emotional states, such as triumph, despair, pride, and shame. Smith and Mackie (2007) defined it by saying "The self-concept is what we think about the self; self-esteem, is the positive or negative evaluations of the self, as in how we feel about it."Self-esteem is an attractive psychological construct because it predicts certain outcomes, such as academic achievement, happiness, satisfaction in marriage and relationships, and criminal behavior. Self-esteem can apply to a specific attribute or globally. Psychologists usually regard self-esteem as an enduring personality characteristic (trait self-esteem), though normal, short-term variations (state self-esteem) also exist. Synonyms or near-synonyms of self-esteem include: self-worth, self-regard, self-respect, and self-integrity. History The concept of self-esteem has its origins in the 18th century, first expressed in the writings of the Scottish enlightenment thinker David Hume. Hume posits that it is important to value and think well of oneself because it serves a motivational function that enables people to explore their full potential.The identification of self-esteem as a distinct psychological construct has its origins in the work of philosopher, psychologist, geologist, and anthropologist William James (1892). James identified multiple dimensions of the self, with two levels of hierarchy: processes of knowing (called the "I-self") and the resulting knowledge about the self (the "Me-self"). The observation about the self and storage of those observations by the I-self creates three types of knowledge, which collectively account for the Me-self, according to James. These are the material self, social self, and spiritual self. The social self comes closest to self-esteem, comprising all characteristics recognized by others. The material self consists of representations of the body and possessions and the spiritual self of descriptive representations and evaluative dispositions regarding the self. This view of self-esteem as the collection of an individuals attitudes toward itself remains today.In the mid-1960s, social psychologist Morris Rosenberg defined self-esteem as a feeling of self-worth and developed the Rosenberg self-esteem scale (RSES), which became the most-widely used scale to measure self-esteem in the social sciences.In the early 20th century, the behaviorist movement minimized introspective study of mental processes, emotions, and feelings, replacing introspection with objective study through experiments on behaviors observed in relation with the environment. Behaviorism viewed the human being as an animal subject to reinforcements, and suggested placing psychology as an experimental science, similar to chemistry or biology. As a consequence, clinical trials on self-esteem were overlooked, since behaviorists considered the idea less liable to rigorous measurement. In the mid-20th century, the rise of phenomenology and humanistic psychology led to renewed interest in self-esteem. Self-esteem then took a central role in personal self-actualization and in the treatment of psychic disorders. Psychologists started to consider the relationship between psychotherapy and the personal satisfaction of people with high self-esteem as useful to the field. This led to new elements being introduced to the concept of self-esteem, including the reasons why people tend to feel less worthy and why people become discouraged or unable to meet challenges by themselves.In 1992 the political scientist Francis Fukuyama associated self-esteem with what Plato called thymos – the "spiritedness" part of the Platonic soul.From 1997, the core self-evaluations approach included self-esteem as one of four dimensions that comprise ones fundamental appraisal of oneself – along with locus of control, neuroticism, and self-efficacy. The concept of core self-evaluations as first examined by Judge, Locke, and Durham (1997), has since proven to have the ability to predict job satisfaction and job performance. Self-esteem may be essential to self-evaluation. In public policy The importance of self-esteem gained endorsement from some government and non-government groups starting around the 1970s, such that one can speak of a self-esteem movement. This movement can be used as an example of promising evidence that psychological research can have an effect on forming public policy. The underlying idea of the movement was that low self-esteem was the root of problems for individuals, making it the root of societal problems and dysfunctions. A leading figure of the movement, psychologist Nathaniel Branden, stated: "[I] cannot think of a single psychological problem – from anxiety and depression, to fear of intimacy or of success, to spouse battery or child molestation – that is not traced back to the problem of low self-esteem".: 3 Self-esteem was believed to be a cultural phenomenon of Western individualistic societies since low self-esteem was not found in collectivist countries such as Japan. Concern about low self-esteem and its many presumed negative consequences led California assemblyman John Vasconcellos to work to set up and fund the Task Force on Self-Esteem and Personal and Social Responsibility, in California, in 1986. Vasconcellos argued that this task force could combat many of the states problems – from crime and teen pregnancy to school underachievement and pollution. He compared increasing self-esteem to giving out a vaccine for a disease: it could help protect people from being overwhelmed by lifes challenges. The task force set up committees in many California counties and formed a committee of scholars to review the available literature on self-esteem. This committee found very small associations between low self-esteem and its assumed consequences, ultimately showing that low self-esteem was not the root of all societal problems and not as important as the committee had originally thought. However, the authors of the paper that summarized the review of the literature still believed that self-esteem is an independent variable that affects major social problems. The task force disbanded in 1995, and the National Council for Self-Esteem and later the National Association for Self-Esteem (NASE) was established, taking on the task forces mission. Vasconcellos and Jack Canfield were members of its advisory board in 2003, and members of its masters coalition included Anthony Robbins, Bernie Siegel, and Gloria Steinem. Theories Many early theories suggested that self-esteem is a basic human need or motivation. American psychologist Abraham Maslow included self-esteem in his hierarchy of human needs. He described two different forms of "esteem": the need for respect from others in the form of recognition, success, and admiration, and the need for self-respect in the form of self-love, self-confidence, skill, or aptitude. Respect from others was believed to be more fragile and easily lost than inner self-esteem. According to Maslow, without the fulfillment of the self-esteem need, individuals will be driven to seek it and unable to grow and obtain self-actualization. Maslow also states that the healthiest expression of self-esteem "is the one which manifests in the respect we deserve for others, more than renown, fame, and flattery". Modern theories of self-esteem explore the reasons humans are motivated to maintain a high regard for themselves. Sociometer theory maintains that self-esteem evolved to check ones level of status and acceptance in ones social group. According to Terror Management Theory, self-esteem serves a protective function and reduces anxiety about life and death.Carl Rogers (1902–1987), an advocate of humanistic psychology, theorized the origin of many peoples problems to be that they despise themselves and consider themselves worthless and incapable of being loved. This is why Rogers believed in the importance of giving unconditional acceptance to a client and when this was done it could improve the clients self-esteem. In his therapy sessions with clients, he offered positive regard no matter what. Indeed, the concept of self-esteem is approached since then in humanistic psychology as an inalienable right for every person, summarized in the following sentence: Every human being, with no exception, for the mere fact to be it, is worthy of unconditional respect of everybody else; he deserves to esteem himself and to be esteemed. Measurement Self-esteem is typically assessed using self-report inventories. One of the most widely used instruments, the Rosenberg self-esteem scale (RSES) is a 10-item self-esteem scale score that requires participants to indicate their level of agreement with a series of statements about themselves. An alternative measure, the Coopersmith Inventory uses a 50-question battery over a variety of topics and asks subjects whether they rate someone as similar or dissimilar to themselves. If a subjects answers demonstrate solid self-regard, the scale regards them as well adjusted. If those answers reveal some inner shame, it considers them to be prone to social deviance.Implicit measures of self-esteem began to be used in the 1980s. These rely on indirect measures of cognitive processing thought to be linked to implicit self-esteem, including the name letter task (or initial preference task) and the Implicit Association Task.Such indirect measures are designed to reduce awareness of the process of assessment. When using them to assess implicit self-esteem, psychologists apply self-relevant stimuli to the participant and then measure how quickly a person identifies positive or negative stimuli. For example, if a woman was given the self-relevant stimuli of female and mother, psychologists would measure how quickly she identified the negative word, evil, or the positive word, kind. Development across lifespan Experiences in a persons life are a major source of how self-esteem develops. In the early years of a childs life, parents have a significant influence on self-esteem and can be considered the main source of positive and negative experiences a child will have. Unconditional love from parents helps a child develop a stable sense of being cared for and respected. These feelings translate into later effects on self-esteem as the child grows older. Students in elementary school who have high self-esteem tend to have authoritative parents who are caring, supportive adults who set clear standards for their child and allow them to voice their opinion in decision making. Although studies thus far have reported only a correlation of warm, supportive parenting styles (mainly authoritative and permissive) with children having high self-esteem, these parenting styles could easily be thought of as having some causal effect in self-esteem development. Childhood experiences that contribute to healthy self-esteem include being listened to, being spoken to respectfully, receiving appropriate attention and affection and having accomplishments recognized and mistakes or failures acknowledged and accepted. Experiences that contribute to low self-esteem include being harshly criticized, being physically, sexually or emotionally abused, being ignored, ridiculed or teased or being expected to be "perfect" all the time.During school-aged years, academic achievement is a significant contributor to self-esteem development. Consistently achieving success or consistently failing will have a strong effect on students individual self-esteem. However, students can also experience low self-esteem while in school. For example, they may not have academic achievements, or they live in a troubled environment outside of school. Issues like the ones previously stated, can cause adolescents to doubt themselves. Social experiences are another important contributor to self-esteem. As children go through school, they begin to understand and recognize differences between themselves and their classmates. Using social comparisons, children assess whether they did better or worse than classmates in different activities. These comparisons play an important role in shaping the childs self-esteem and influence the positive or negative feelings they have about themselves. As children go through adolescence, peer influence becomes much more important. Adolescents make appraisals of themselves based on their relationships with close friends. Successful relationships among friends are very important to the development of high self-esteem for children. Social acceptance brings about confidence and produces high self-esteem, whereas rejection from peers and loneliness brings about self-doubts and produces low self-esteem.Adolescence shows an increase in self-esteem that continues to increase in young adulthood and middle age. A decrease is seen from middle age to old age with varying findings on whether it is a small or large decrease. Reasons for the variability could be because of differences in health, cognitive ability, and socioeconomic status in old age. No differences have been found between males and females in their development of self-esteem. Multiple cohort studies show that there is not a difference in the life-span trajectory of self-esteem between generations due to societal changes such as grade inflation in education or the presence of social media.High levels of mastery, low risk taking, and better health are ways to predict higher self-esteem. In terms of personality, emotionally stable, extroverted, and conscientious individuals experience higher self-esteem. These predictors have shown us that self-esteem has trait-like qualities by remaining stable over time like personality and intelligence. However, this does not mean it can not be changed. Hispanic adolescents have a slightly lower self-esteem than their black and white peers, but then slightly higher levels by age 30. African Americans have a sharper increase in self-esteem in adolescence and young adulthood compared to Whites. However, during old age, they experience a more rapid decline in self-esteem. Shame Shame can be a contributor to those with problems of low self-esteem. Feelings of shame usually occur because of a situation where the social self is devalued, such as a socially evaluated poor performance. A poor performance leads to higher responses of psychological states that indicate a threat to the social self namely a decrease in social self-esteem and an increase in shame. This increase in shame can be helped with self-compassion. Real self, ideal self, and dreaded self There are three levels of self-evaluation development in relation to the real self, ideal self, and the dreaded self. The real, ideal, and dreaded selves develop in children in a sequential pattern on cognitive levels. Moral judgment stages: Individuals describe their real, ideal, and dreaded selves with stereotypical labels, such as "nice" or "bad". Individuals describe their ideal and real selves in terms of disposition for actions or as behavioral habits. The dreaded self is often described as being unsuccessful or as having bad habits. Ego development stages: Individuals describe their ideal and real selves in terms of traits that are based on attitudes as well as actions. The dreaded self is often described as having failed to meet social expectations or as self-centered. Self-understanding stages: Individuals describe their ideal and real selves as having unified identities or characters. Descriptions of the dreaded self focus on a failure to live up to ones ideals or role expectations often because of real world problems.This development brings with it increasingly complicated and encompassing moral demands. This level is where individuals self-esteems can suffer because they do not feel as though they are living up to certain expectations. This feeling will moderately affect ones self-esteem with an even larger effect seen when individuals believe they are becoming their dreaded selves. Types High People with a healthy level of self-esteem: Firmly believe in certain values and principles, and are ready to defend them even when finding opposition, feeling secure enough to modify them in light of experience. Are able to act according to what they think to be the best choice, trusting their own judgment, and not feeling guilty when others do not like their choice. Do not lose time worrying excessively about what happened in the past, nor about what could happen in the future. They learn from the past and plan for the future, but live in the present intensely. Fully trust in their capacity to solve problems, not hesitating after failures and difficulties. They ask others for help when they need it. Consider themselves equal in dignity to others, rather than inferior or superior, while accepting differences in certain talents, personal prestige or financial standing. Understand how they are an interesting and valuable person for others, at least for those with whom they have a friendship. Resist manipulation, collaborate with others only if it seems appropriate and convenient. Admit and accept different internal feelings and drives, either positive or negative, revealing those drives to others only when they choose. Are able to enjoy a great variety of activities. Are sensitive to feelings and needs of others; respect generally accepted social rules, and claim no right or desire to prosper at others expense. Can work toward finding solutions and voice discontent without belittling themselves or others when challenges arise. Secure vs. defensive A person can have high self-esteem and hold it confidently where they do not need reassurance from others to maintain their positive self-view, whereas others with defensive high self-esteem may still report positive self-evaluations on the Rosenberg Scale, as all high self-esteem individuals do; however, their positive self-views are fragile and vulnerable to criticism. Defensive high self-esteem individuals internalize subconscious self-doubts and insecurities, causing them to react very negatively to any criticism they may receive. There is a need for constant positive feedback from others for these individuals to maintain their feelings of self-worth. The necessity of repeated praise can be associated with boastful, arrogant behavior or sometimes even aggressive and hostile feelings toward anyone who questions the individuals self-worth, an example of threatened egotism.The Journal of Educational Psychology conducted a study in which they used a sample of 383 Malaysian undergraduates participating in work integrated learning (WIL) programs across five public universities to test the relationship between self-esteem and other psychological attributes such as self-efficacy and self-confidence. The results demonstrated that self-esteem has a positive and significant relationship with self-confidence and self-efficacy since students with higher self-esteem had better performances at university than those with lower self-esteem. It was concluded that higher education institutions and employers should emphasize the importance of undergraduates self-esteem development. Implicit and explicit Implicit self-esteem refers to a persons disposition to evaluate themselves positively or negatively in a spontaneous, automatic, or unconscious manner. It contrasts with explicit self-esteem, which entails more conscious and reflective self-evaluation. Both explicit self-esteem and implicit self-esteem are theoretically subtypes of self-esteem proper. However, the validity of implicit self-esteem as a construct is highly questionable, given not only its weak or nonexistent correlation with explicit self-esteem and informant ratings of self-esteem, but also the failure of multiple measures of implicit self-esteem to correlate with each other.As present, there is little scientific evidence that self-esteem can be reliably or validly measured through implicit means. Narcissism and threatened egotism Narcissism is a disposition people may have that represents an excessive love for ones self. It is characterized by an inflated view of self-worth. Individuals who score high on narcissism measures, Robert Raskins Narcissistic Personality Inventory, would likely select true to such statements as "If I ruled the world, it would be a much better place." There is only a moderate correlation between narcissism and self-esteem; that is to say that an individual can have high self-esteem but low narcissism or can be a conceited, obnoxious person and score high self-esteem and high narcissism. However, when correlation analysis is restricted to the sense of superiority or self-admiration aspects of narcissism, correlations between narcissism and self-esteem become strong (usually at or around r =.50, but sometimes up to β =.86). Moreover, self-esteem is positively correlated with a sense of superiority even when controlling for overall narcissism.In addition to exaggerated regard for oneself, however, narcissism is additionally defined by such characteristics as entitlement, exploitativeness and dominance. Additionally, while positive self-image is a shared characteristic of narcissism and self-esteem, narcissistic self-appraisals are exaggerated and limited to agentic traits (intellect, talent, etc.), whereas in non-narcissistic self-esteem, positive views of the self compared with others are relatively modest and sample equally from the agentic and communal (morality, honesty, etc.) domains. Thus, while sharing positive self-regard as a main feature, and while narcissism is defined by high self-esteem, the two constructs are not interchangeable. Threatened egotism is characterized as a response to criticism that threatens the ego of narcissists; they often react in a hostile and aggressive manner. Low Low self-esteem can result from various factors, including genetic factors, physical appearance or weight, mental health issues, socioeconomic status, significant emotional experiences, social stigma, peer pressure or bullying.A person with low self-esteem may show some of the following characteristics: Heavy self-criticism and dissatisfaction. Hypersensitivity to criticism with resentment against critics and feelings of being attacked. Chronic indecision and an exaggerated fear of mistakes. Excessive will to please and unwillingness to displease any petitioner. Perfectionism, which can lead to frustration when perfection is not achieved. Neurotic guilt, dwelling on or exaggerating the magnitude of past mistakes. Floating hostility and general defensiveness and irritability without any proximate cause. Pessimism and a general negative outlook. Envy, invidiousness, or general resentment. Sees temporary setbacks as permanent, intolerable conditions.Individuals with low self-esteem tend to be critical of themselves. Some depend on the approval and praise of others when evaluating self-worth. Others may measure their likability in terms of successes: others will accept themselves if they succeed but will not if they fail. People with chronic low self esteem are at a higher risk for experiencing psychotic disorders; and this behavior is closely linked to forming psychotic symptoms as well. Treatments Metacognitive therapy, EMDR technique, mindfulness-based cognitive therapy, rational emotive behavior therapy, cognitive behavioral therapy and trait and construct therapies have been shown to improve the patients self-esteem. The three states This classification proposed by Martin Ross distinguishes three states of self-esteem compared to the "feats" (triumphs, honors, virtues) and the "anti-feats" (defeats, embarrassment, shame, etc.) of the individuals. Shattered The individual does not regard themselves as valuable or lovable. They may be overwhelmed by defeat, or shame, or see themselves as such, and they name their "anti-feat". For example, if they consider that being over a certain age is an anti-feat, they define themselves with the name of their anti-feat, and say, "I am old". They express actions and feelings such as pity, insulting themselves, and they may become paralyzed by their sadness. Vulnerable The individual has a generally positive self-image. However, their self-esteem is also vulnerable to the perceived risk of an imminent anti-feat (such as defeat, embarrassment, shame, discredit), consequently, they are often nervous and regularly use defense mechanisms. A typical protection mechanism of those with vulnerable self-esteem may consist in avoiding decision-making. Although such individuals may outwardly exhibit great self-confidence, the underlying reality may be just the opposite: the apparent self-confidence is indicative of their heightened fear of anti-feats and the fragility of their self-esteem. They may also try to blame others to protect their self-image from situations that would threaten it. They may employ defense mechanisms, including attempting to lose at games and other competitions in order to protect their self-image by publicly dissociating themselves from a need to win, and asserting an independence from social acceptance which they may deeply desire. In this deep fear of being unaccepted by an individuals peers, they make poor life choices by making risky decisions. Strong People with strong self-esteem have a positive self-image and enough strength so that anti-feats do not subdue their self-esteem. They have less fear of failure. These individuals appear humble, cheerful, and this shows a certain strength not to boast about feats and not to be afraid of anti-feats. They are capable of fighting with all their might to achieve their goals because, if things go wrong, their self-esteem will not be affected. They can acknowledge their own mistakes precisely because their self-image is strong, and this acknowledgment will not impair or affect their self-image. They live with less fear of losing social prestige, and with more happiness and general well-being. However, no type of self-esteem is indestructible, and due to certain situations or circumstances in life, one can fall from this level into any other state of self-esteem. Contingent vs. non-contingent A distinction is made between contingent (or conditional) and non-contingent (or unconditional) self-esteem. Contingent self-esteem is derived from external sources, such as what others say, ones success or failure, ones competence, or relationship-contingent self-esteem. Therefore, contingent self-esteem is marked by instability, unreliability, and vulnerability. Persons lacking a non-contingent self-esteem are "predisposed to an incessant pursuit of self-value". However, because the pursuit of contingent self-esteem is based on receiving approval, it is doomed to fail, as no one receives constant approval, and disapproval often evokes depression. Furthermore, fear of disapproval inhibits activities in which failure is possible. Non-contingent self-esteem is described as true, stable, and solid. It springs from a belief that one is "acceptable period, acceptable before life itself, ontologically acceptable". Belief that one is "ontologically acceptable" is to believe that ones acceptability is "the way things are without contingency". In this belief, as expounded by theologian Paul Tillich, acceptability is not based on a persons virtue. It is an acceptance given "in spite of our guilt, not because we have no guilt".Psychiatrist Thomas A Harris drew on Tillich for his classic Im OK – Youre OK that addresses non-contingent self-esteem. Harris translated Tillichs "acceptable" by the vernacular OK, a term that means "acceptable". The Christian message, said Harris, is not "YOU CAN BE OK, IF"; it is "YOU ARE ACCEPTED, unconditionally".A secure non-contingent self-esteem springs from the belief that one is ontologically acceptable and accepted. Domain-specific self-esteem Whereas global self-esteem addresses how individuals appraise themselves in their entirety, domain-specific self-esteem facets relate to how they appraise themselves in various pertinent domains of life. Such functionally distinct facets of self-esteem may comprise self-evaluations in social, emotional, body-related, school performance-related, and creative-artistic domains.They have been found to be predictive of outcomes related to psychological functioning, health, education, and work. Low self-esteem in the social domain (i.e., self-perceived social competence), for example, has been repeatedly identified as a risk factor for bullying victimization. Importance Abraham Maslow states that psychological health is not possible unless the essential core of the person is fundamentally accepted, loved and respected by others and by oneself. Self-esteem allows people to face life with more confidence, benevolence, and optimism, and thus easily reach their goals and self-actualize.Self-esteem may make people convinced they deserve happiness. Understanding this is fundamental, and universally beneficial, since the development of positive self-esteem increases the capacity to treat other people with respect, benevolence and goodwill, thus favoring rich interpersonal relationships and avoiding destructive ones. For Erich Fromm, the love of others and love of ourselves are not alternatives. On the contrary, an attitude of love toward themselves will be found in all those who are capable of loving others. Self-esteem allows creativity at the workplace and is a specially critical condition for teaching professions.José-Vicente Bonet claims that the importance of self-esteem is obvious as a lack of self-esteem is, he says, not a loss of esteem from others, but self-rejection. Bonet claims that this corresponds to major depressive disorder. Freud also claimed that the depressive has suffered "an extraordinary diminution in his self-regard, an impoverishment of his ego on a grand scale... He has lost his self-respect".The Yogyakarta Principles, a document on international human rights law, addresses the discriminatory attitude toward LGBT people that makes their self-esteem low to be subject to human rights violation including human trafficking. The World Health Organization recommends in "Preventing Suicide", published in 2000, that strengthening students self-esteem is important to protect children and adolescents against mental distress and despondency, enabling them to cope adequately with difficult and stressful life situations.Other than increased happiness, higher self-esteem is also known to correlate with a better ability to cope with stress and a higher likeliness of taking on difficult tasks relative to those with low self-esteem. Correlations From the late 1970s to the early 1990s many Americans assumed as a matter of course that students self-esteem acted as a critical factor in the grades that they earned in school, in their relationships with their peers, and in their later success in life. Under this assumption, some American groups created programs which aimed to increase the self-esteem of students. Until the 1990s, little peer-reviewed and controlled research took place on this topic. Peer-reviewed research undertaken since then has not validated previous assumptions. Recent research indicates that inflating students self-esteems in and of itself has no positive effect on grades. Roy Baumeister has shown that inflating self-esteem by itself can actually decrease grades. The relationship involving self-esteem and academic results does not signify that high self-esteem contributes to high academic results. It simply means that high self-esteem may be accomplished as a result of high academic performance due to the other variables of social interactions and life events affecting this performance.Attempts by pro-esteem advocates to encourage self-pride in students solely by reason of their

Self-esteem

uniqueness as human beings will fail if feelings of well-being are not accompanied by well-doing. It is only when students engage in personally meaningful endeavors for which they can be justifiably proud that self-confidence grows, and it is this growing self-assurance that in turn triggers further achievement.High self-esteem has a high correlation to self-reported happiness; whether this is a causal relationship has not been established. The relationship between self-esteem and life satisfaction is stronger in individualistic cultures.Additionally, self-esteem has been found to be related to forgiveness in close relationships, in that people with high self-esteem will be more forgiving than people with low self-esteem.High self-esteem does not prevent children from smoking, drinking, taking drugs, or engaging in early sex. Mental Health Self-esteem has been associated with several mental health conditions, including depression, anxiety, and eating disorders. For example, low self-esteem may increase the likelihood that people who experience dysfunctional thoughts will develop symptoms of depression. In contrast, high self-esteem may protect against the development of mental health conditions, with research finding that high self-esteem reduces the chances of bulimia and anxiety. Neuroscience In research conducted in 2014 by Robert S. Chavez and Todd F. Heatherton, it was found that self-esteem is related to the connectivity of the frontostriatal circuit. The frontostriatal pathway connects the medial prefrontal cortex, which deals with self-knowledge, to the ventral striatum, which deals with feelings of motivation and reward. Stronger anatomical pathways are correlated with higher long-term self-esteem, while stronger functional connectivity is correlated with higher short-term self-esteem. Criticism and controversy The American psychologist Albert Ellis criticized on numerous occasions the concept of self-esteem as essentially self-defeating and ultimately destructive. Although acknowledging the human propensity and tendency to ego rating as innate, he has critiqued the philosophy of self-esteem as unrealistic, illogical and self- and socially destructive – often doing more harm than good. Questioning the foundations and usefulness of generalized ego strength, he has claimed that self-esteem is based on arbitrary definitional premises, and overgeneralized, perfectionistic and grandiose thinking. Acknowledging that rating and valuing behaviors and characteristics is functional and even necessary, he sees rating and valuing human beings totality and total selves as irrational and unethical. The healthier alternative to self-esteem according to him is unconditional self-acceptance and unconditional other-acceptance. Rational Emotive Behavior Therapy is a psychotherapy based on this approach. "There seem to be only two clearly demonstrated benefits of high self-esteem....First, it increases initiative, probably because it lends confidence. People with high self-esteem are more willing to act on their beliefs, to stand up for what they believe in, to approach others, to risk new undertakings. (This unfortunately includes being extra willing to do stupid or destructive things, even when everyone else advises against them.)...It can also lead people to ignore sensible advice as they stubbornly keep wasting time and money on hopeless causes" False attempts For persons with low self-esteem, any positive stimulus will temporarily raise self-esteem. Therefore, possessions, sex, success, or physical appearance will produce the development of self-esteem, but the development is ephemeral at best. Such attempts to raise ones self-esteem by positive stimulus produce a "boom or bust" pattern. "Compliments and positive feedback" produce a boost, but a bust follows a lack of such feedback. For a person whose "self-esteem is contingent", success is "not extra sweet", but "failure is extra bitter". As narcissism Life satisfaction, happiness, healthy behavioral practices, perceived efficacy, and academic success and adjustment have been associated with having high levels of self-esteem (Harter, 1987; Huebner, 1991; Lipschitz-Elhawi & Itzhaky, 2005; Rumberger 1995; Swenson & Prelow, 2005; Yarcheski & Mahon, 1989).: 270  However, a common mistake is to think that loving oneself is necessarily equivalent to narcissism, as opposed for example to what Erik Erikson speaks of as "a post-narcissistic love of the ego". People with a healthy self-esteem accept and love themselves unconditionally, acknowledging both virtues and faults in the self, and yet, in spite of everything, are able to continue to love themselves. In narcissists, by contrast, an " uncertainty about their own worth gives rise to...a self-protective, but often totally spurious, aura of grandiosity" – producing the class "of narcissists, or people with very high, but insecure, self-esteem... fluctuating with each new episode of social praise or rejection.": 479 Narcissism can thus be seen as a symptom of fundamentally low self-esteem, that is, lack of love towards oneself, but often accompanied by "an immense increase in self-esteem" based on "the defense mechanism of denial by overcompensation." "Idealized love of self...rejected the part of him" that he denigrates – "this destructive little child" within. Instead, the narcissist emphasizes their virtues in the presence of others, just to try to convince themself that they are a valuable person and to try to stop feeling ashamed for their faults; such "people with unrealistically inflated self-views, which may be especially unstable and highly vulnerable to negative information,...tend to have poor social skills.": 126 See also References Further reading Baumeister, Roy F. (2001). "Violent Pride: Do people turn violent because of self-hate or self-love?," in Scientific American, 284, No. 4, pp. 96–101; April 2001. Branden, N. (1969). The Psychology of Self-Esteem. New York: Bantam. Branden, N. (2001). The psychology of self-esteem: a revolutionary approach to self-understanding that launched a new era in modern psychology. San Francisco: Jossey-Bass, 2001. ISBN 0787945269 Burke, C. (2008) "Self-esteem: Why?; Why not?," New York: 2008 Crocker J.; Park L. E. (2004). "The costly pursuit of self-esteem". Psychological Bulletin. 130 (3): 392–414. doi:10.1037/0033-2909.130.3.392. PMID 15122925. Franklin, Richard L. (1994). "Overcoming The Myth of Self-Worth: Reason and Fallacy in What You Say to Yourself." ISBN 0963938703 Hill, S.E. & Buss, D.M. (2006). "The Evolution of Self-Esteem." In Michael Kernis, (Ed.), Self Esteem: Issues and Answers: A Sourcebook of Current Perspectives.. Psychology Press:New York. 328–33. Full text Lerner, Barbara (1985). "Self-Esteem and Excellence: The Choice and the Paradox," American Educator, Winter 1985. Mecca, Andrew M., et al., (1989). The Social Importance of Self-esteem University of California Press, 1989. (ed; other editors included Neil J. Smelser and John Vasconcellos) Mruk, C. (2006). Self-Esteem research, theory, and practice: Toward a positive psychology of self-esteem (3rd ed.). New York: Springer. Rodewalt F.; Tragakis M. W. (2003). "Self-esteem and self-regulation: Toward optimal studies of self-esteem". Psychological Inquiry. 14 (1): 66–70. doi:10.1207/s15327965pli1401_02. Ruggiero, Vincent R. (2000). "Bad Attitude: Confronting the Views That Hinder Students Learning" American Educator. Sedikides, C., & Gregg. A. P. (2003). "Portraits of the self." In M. A. Hogg & J. Cooper (Eds.), Sage handbook of social psychology (pp. 110–38). London: Sage Publications. Twenge, Jean M. (2007). Generation Me: Why Todays Young Americans Are More Confident, Assertive, Entitled – and More Miserable Than Ever Before. Free Press. ISBN 978-0743276986

Compulsive hoarding

Compulsive hoarding, also known as hoarding disorder, Plyushkins disorder, is a mental disorder characterised by accumulation of possessions due to excessive acquisition of or difficulty discarding them, regardless of their actual value, leading to clinically significant distress or impairment in personal, family, social, educational, occupational or other important areas of functioning. Excessive acquisition is characterized by repetitive urges or behaviours related to amassing or buying items. Difficulty discarding possessions is characterized by a perceived need to save items and distress associated with discarding them. Accumulation of possessions results in living spaces becoming cluttered to the point that their use or safety is compromised. It is recognised by the eleventh revision of the International Classification of Diseases (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Prevalence rates are estimated at 2% to 5% in adults, though the condition typically manifests in childhood with symptoms worsening in advanced age, at which point collected items have grown excessive and family members who would otherwise help to maintain and control the levels of clutter have either died or moved away.People with hoarding disorder commonly live with other complex and/or psychological disorders such as depression, anxiety, obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). Other factors often associated with hoarding include alcohol dependence and paranoid, schizotypal and avoidance traits. Differential diagnosis Collecting and hoarding may seem similar, but there are distinct characteristics that set the behaviors apart. Collecting is a hobby often involving the targeted search and acquisition of specific items that form—at least from the perspective of the collector—a greater appreciation, deeper understanding, or increased synergistic value when combined with other similar items. Hoarding, by contrast, typically appears haphazard and involves the overall acquiring of common items that would not be especially meaningful to the person who is gathering such items in large quantities. People who hoard commonly keep items that hold little to no true meaning or value to most others, unlike some collectors, whose items may be of great value to select people. Most hoarders are disorganized, and their living areas are crowded and in disarray. Most collectors can afford to store their items systematically or to have enough room to display their collections. Age, mental state, or finances have caused some collectors to fall into a hoarding state. Clutter Image Rating A UK charity called HoardingUK, has found that people have very different ideas about what it means to have a cluttered home. For some, a small pile of things in the corner of an otherwise well-ordered room constitutes serious clutter. For others, only when the narrow pathways make it hard to get through a room does the clutter register. To ensure an accurate sense of a clutter problem, they created the Clutter Image Rating, a series of pictures of rooms in various stages of clutter – from completely clutter-free to very severely cluttered designed to encourage people to get support. Studies In a 2010 study using data from self-reports of hoarding behavior from 751 participants, it was found most reported the onset of their hoarding symptoms between the ages of 11 and 20 years old, with 70% reporting the behaviors before the age of 21. Fewer than 4% of people reported the onset of their symptoms after the age of 40. The data showed that compulsive hoarding usually begins early, but often does not become more prominent until after age 40. Different reasons have been given for this, such as the effects of family presence earlier in life and limits on hoarding imposed by housing situation and lifestyle. The understanding of early onset hoarding behavior may help in the future to better distinguish hoarding behavior from "normal" childhood collecting behaviors.A second key part of this study was to determine if stressful life events are linked to the onset of hoarding symptoms. Similar to self-harming, traumatized persons may create a problem for themselves in order to avoid their real anxiety or trauma. Facing their real issues may be too difficult for them, so they create an artificial problem (in their case, hoarding) and prefer to battle with it rather than determine, face, or do something about their real anxieties. Hoarders may suppress their psychological pain by hoarding. The study shows that adults who hoard report a greater lifetime incidence of having possessions taken by force, forced sexual activity as either an adult or a child, including forced sexual intercourse, and being physically handled roughly during childhood, thus proving traumatic events are positively correlated with the severity of hoarding. For each five years of life the participant would rate from 1 to 4, 4 being the most severe, the severity of their hoarding symptoms. Of the participants, 548 reported a chronic course, 159 an increasing course and 39 people, a decreasing course of illness. The incidents of increased hoarding behavior were usually correlated to five categories of stressful life events.Although excessive acquiring is not a diagnostic criterion of hoarding, at least two-thirds of individuals with hoarding disorder excessively acquire possessions. Having a more anxiously attached interpersonal style is associated with more compulsive buying and greater acquisition of free items and these relationships are mediated by stronger distress intolerance and greater anthropomorphism. Anthropomorphism has been shown to increase both the sentimental value and perceived utility of items. These findings indicate that individuals may over-value their possessions to compensate for thwarted interpersonal needs. Feeling alone and/or disconnected from others may impair peoples ability to tolerate distress and increase peoples tendencies to see human-like qualities in objects. The humanness of items may increase their perceived value and individuals may acquire these valued objects to alleviate distress. Individuals with hoarding problems have been shown to have greater interpersonal problems than individuals who only excessively acquire possessions, which provides some support for the assumption that individuals with hoarding problems may have a stronger motivation to hang onto possessions for support. As possessions cannot provide support in the way humans can and because saving excessively can frustrate other people due to its impact on their quality of life, individuals with hoarding disorder may be caught in a feedback loop. They may save to alleviate distress, but this saving may cause distress, which may lead them to keep saving to alleviate the distress. Treatment Only 5% of people with hoarding behaviours receive help (Singh, 2012) and the interventions they do receive focus on clearing items, not treating the disorder. Cognitive-behavioral therapy (CBT) is a commonly implemented therapeutic intervention for compulsive hoarding. As part of cognitive behavior therapy, the therapist may help the patient to: Discover why one is compelled to hoard. Learn to organize possessions in order to decide what to discard. Develop decision-making skills. Declutter the home during in-home visits by a therapist or professional organizer. Gain and perform relaxation skills. Attend family and/or group therapy. Be open to trying psychiatric hospitalization if the hoarding is serious. Have periodic visits and consultations to keep a healthy lifestyle.This modality of treatment usually involves exposure and response prevention to situations that cause anxiety and cognitive restructuring of beliefs related to hoarding. Furthermore, research has also shown that certain CBT protocols have been more effective in treatment than others. CBT programs that specifically address the motivation of the affected person, organization, acquiring new clutter, and removing current clutter from the home have shown promising results. This type of treatment typically involves in-home work with a therapist combined with between-session homework, the completion of which is associated with better treatment outcomes. Research on internet-based CBT treatments for the disorder (where participants have access to educational resources, cognitive strategies, and chat groups) has also shown promising results both in terms of short- and long-term recovery.Other therapeutic approaches that have been found to be helpful: Motivational interviewing originated in addiction therapy. This method is significantly helpful when used in hoarding cases in which insight is poor and ambivalence to change is marked. Harm reduction rather than symptom reduction. Also borrowed from addiction therapy. The goal is to decrease the harmful implications of the behavior, rather than the hoarding behaviors. Group psychotherapy reduces social isolation and social anxiety and is cost-effective compared to one-on-one intervention. Group CBT tends to have similar outcomes to individual therapy. Although group treatment often does not include home sessions, experimental research suggests that treatment outcomes may be improved if home sessions are included. Individuals have been shown to discard more possessions when in a cluttered environment compared to a tidy environment. Indeed, a meta-analysis found that a greater number of home sessions improves CBT outcomes.Individuals with hoarding behaviors are often described as having low motivation and poor compliance levels, and as being indecisive and procrastinators, which may frequently lead to premature termination (i.e., dropout) or low response to treatment. Therefore, it was suggested that future treatment approaches, and pharmacotherapy in particular, be directed to address the underlying mechanisms of cognitive impairments demonstrated by individuals with hoarding symptoms. Mental health professionals frequently express frustration regarding hoarding cases, mostly due to premature termination and poor response to treatment. Patients are frequently described as indecisive, procrastinators, recalcitrant, and as having low or no motivation, which can explain why many interventions fail to accomplish significant results. To overcome this obstacle, some clinicians recommend accompanying individual therapy with home visits to help the clinician: Likewise, certain cases are assisted by professional organizers as well. In popular culture Maguire, Emily: Love Objects (2021), Allen & Unwin, ISBN 9781760878337 Hoarders - TV series Hoarding: Buried Alive See also Hoarders Alexander Kennedy Miller, hoarded about 30 Stutz automobiles (1906–1993) Collyer brothers, Homer Collyer (1881–1947) and Langley Collyer (1885–1947) Edmund Trebus (1918–2002), participated in TV documentary References Further reading Frost, Randy O.; Steketee, Gail (2011). Stuff: Compulsive Hoarding and the Meaning of Things. Mariner Books. ISBN 9780547487250. Herring, Scott (2014). The Hoarders: Material Deviance in Modern American Culture. Chicago, IL: University of Chicago Press. ISBN 9780226171715. Mapes, Diane. "Engulfed in clutter, hoarders keep heaping it on". NBC News. Article discussing the disorder and its relationship to OCD. Sholl, Jessie (2010). Dirty Secret: A Daughter Comes Clean About Her Mothers Compulsive Hoarding. New York: Simon & Schuster/Gallery Books. ISBN 9781439192535. External links "Measuring". Squalor Survivors. Non-commercial compulsive hoarding forum HoardingUK

Selective mutism

Selective mutism (SM) is an anxiety disorder in which a person who is otherwise capable of speech becomes unable to speak when exposed to specific situations, specific places, or to specific people, one or multiple of which serving as triggers. This is caused by the freeze response. Selective mutism usually co-exists with social anxiety disorder. People with selective mutism stay silent even when the consequences of their silence include shame, social ostracism, or punishment. Signs and symptoms Children and adults with selective mutism are fully capable of speech and understanding language but are completely unable to speak in certain situations, though speech is expected of them. The behaviour may be perceived as shyness or rudeness by others. A child with selective mutism may be completely silent at school for years but speak quite freely or even excessively at home. There is a hierarchical variation among people with this disorder: some people participate fully in activities and appear social but do not speak, others will speak only to peers but not to adults, others will speak to adults when asked questions requiring short answers but never to peers, and still others speak to no one and participate in few, if any, activities presented to them. In a severe form known as "progressive mutism", the disorder progresses until the person with this condition no longer speaks to anyone in any situation, even close family members. To meet DSM-5 criteria for selective mutism, one must exhibit the following: Consistent failure to speak in specific social situations (in which there is an expectation for speaking, e.g., at school) despite speaking in other situations. The disturbance interferes with educational or occupational achievement or with social communication. The duration of the disturbance is at least 1 month (not limited to the first month of school). The failure to speak is not due to a lack of knowledge of the spoken language required in the social situation. The disturbance is not better accounted for by a communication disorder (e.g., childhood-onset fluency disorder) and does not occur exclusively in people with autism spectrum disorders or psychotic disorders such as schizophrenia.Selective mutism is strongly associated with other anxiety disorders, particularly social anxiety disorder. In fact, the majority of children diagnosed with selective mutism also have social anxiety disorder (100% of participants in two studies and 97% in another). Some researchers therefore speculate that selective mutism may be an avoidance strategy used by a subgroup of children with social anxiety disorder to reduce their distress in social situations.Particularly in young children, selective mutism can sometimes be confused with an autism spectrum disorder, especially if the child acts particularly withdrawn around their diagnostician, which can lead to incorrect diagnosis and treatment. Although autistic people may also be selectively mute, they often display other behaviors—stimming, repetitive behaviors, social isolation even among family members (not always answering to name, for example)—that set them apart from a child with selective mutism. Some autistic people may be selectively mute due to anxiety in unfamiliar social situations. If mutism is entirely due to autism spectrum disorder, it cannot be diagnosed as selective mutism as stated in the last item on the list above. The former name elective mutism indicates a widespread misconception among psychologists that selective mute people choose to be silent in certain situations, while the truth is that they often wish to speak but are unable to do so. To reflect the involuntary nature of this disorder, the name was changed to selective mutism in 1994. The incidence of selective mutism is not certain. Due to the poor understanding of this condition by the general public, many cases are likely undiagnosed. Based on the number of reported cases, the figure is commonly estimated to be 1 in 1000, 0.1%. However, a 2002 study in The Journal of the American Academy of Child and Adolescent Psychiatry estimated the incidence to be 0.71%. Other symptoms Besides lack of speech, other common behaviors and characteristics displayed by selectively mute people, according to Dr. Elisa Shipon-Blums findings, include: Shyness, social anxiety, fear of social embarrassment or social isolation and withdrawal Difficulty maintaining eye contact Blank expression and reluctance to smile or incessant smiling Difficulty expressing feelings, even to family members Tendency to worry more than most people of the same age Sensitivity to noise and crowdsOn the flip side, there are some positive traits observed in many cases: Above average intelligence, inquisitiveness, or perception A strong sense of right and wrong Creativity Love for the arts Empathy Sensitivity for other people Causes Selective mutism (SM) is an umbrella term for the condition of otherwise well-developed children or adults who cannot speak or communicate under certain settings. The exact causes that affect each person may be different and yet unknown. There have been attempts to categorize, but there are no definitive answers yet due to the under-diagnosis and small/biased sample sizes. Many people are not diagnosed until late in childhood only because they do not speak at school and therefore fail to accomplish assignments requiring public speaking. Their involuntary silence makes the condition harder to understand or test. Parents often are unaware of the condition since the children may be functioning well at home. Teachers and pediatricians also sometimes mistake it for severe shyness or common stage fright.Most children and adults with selective mutism are hypothesized to have an inherited predisposition to anxiety. They often have inhibited temperaments, which is hypothesized to be the result of over-excitability of the area of the brain called the amygdala. This area receives indications of possible threats and sets off the fight-or-flight response. Behavioral inhibitions, or inhibited temperaments, encompass feelings of emotional distress and social withdrawals. In a 2016 study, the relationship between behavioral inhibition and selective mutism was investigated. Children between the ages of three and 19 with lifetime selective mutism, social phobia, internalizing behavior, and healthy controls were assessed using the parent-rated Retrospective Infant Behavioral Inhibition (RIBI) questionnaire, consisting of 20 questions that addressed shyness and fear, as well as other subscales. The results indicated behavioral inhibition does indeed predispose selective mutism. Corresponding with the researchers’ hypothesis, children diagnosed with long-term selective mutism had a higher behavioral inhibition score as an infant. This is indicative of the positive correlation between behavioral inhibition and selective mutism. Given the very high incidence of social anxiety disorder within selective mutism (as high as 100% in some studies), it is possible that social anxiety disorder causes selective mutism. Some children or adults with selective mutism may have trouble processing sensory information. This could cause anxiety and a sense of being overwhelmed in unfamiliar situations, which may cause the child or adult to "shut down" and not be able to speak (something that some autistic people also experience). Many children or adults with selective mutism have some auditory processing difficulties. About 20–30% of children or adults with selective mutism have speech or language disorders that add stress to situations in which the child is expected to speak. Despite the change of name from "elective" to "selective", a common misconception remains that a selectively mute child is defiant or stubborn. In fact, children with selective mutism have a lower rate of oppositional behavior than their peers in a school setting. Some previous studies on the subject of selective mutism have been dismissed as containing serious flaws in their design. According to a more recent systematic study it is believed that children or adults who have selective mutism are not more likely than other children or adults to have a history of early trauma or stressful life events. Many children or adults who have selective mutism almost always speak confidently in some situations. Treatment Contrary to popular belief, people with selective mutism do not necessarily improve with age. Effective treatment is necessary for a child to develop properly. Without treatment, selective mutism can contribute to chronic depression, further anxiety, and other social and emotional problems.Consequently, treatment at an early age is important. If not addressed, selective mutism tends to be self-reinforcing. Others may eventually expect an affected child to not speak and therefore stop attempting to initiate verbal contact. Alternatively, they may pressure the child to talk, increasing their anxiety levels in situations where speech is expected. Due to these problems, a change of environment may be a viable consideration. However, changing school is worth considering only if the alternative environment is highly supportive, otherwise a whole new environment could also be a social shock for the individual or deprive them of any friends or support they have currently. Regardless of the cause, increasing awareness and ensuring an accommodating, supportive environment are the first steps towards effective treatment. Most often affected children do not have to change schools or classes and have no difficulty keeping up except on the communication and social front. Treatment in teenage or adult years can be more difficult because the affected individual has become accustomed to being mute, and lacks social skills to respond to social cues.The exact treatment depends on the persons age, any comorbid mental illnesses, and a number of other factors. For instance, stimulus fading is typically used with younger children because older children and teenagers recognize the situation as an attempt to make them speak, and older people with this condition and people with depression are more likely to need medication.Like other disabilities, adequate accommodations are needed for those with the condition to succeed at school, work, and in the home. Under the U.S. federal law and the Individuals with Disabilities Education Act (IDEA), those with the disorder qualify for services based upon the fact that they have an impairment that hinders their ability to speak, thus disrupting their lives. This assistance is typically documented in the form of an Individualized Education Program (IEP). Post-secondary accommodations are also available for people with disabilities.Under another law, Section 504 of the Rehabilitation Act of 1973, public school districts are required to provide a free, appropriate public education to every "qualified handicapped person" residing within their jurisdiction. If the child is found to have impairments that substantially limit a major life activity (in this case, learning), the education agency has to decide what related aids or services are required to provide equal access to the learning environment.Social Communication Anxiety Treatment (S-CAT) is a common treatment approach by professionals and has proven to be successful. S-CAT integrates components of behavioral-therapy, cognitive-behavioral therapy (CBT), and an insight-oriented approach to increase social communication and promote social confidence. Tactics such as systemic desensitization, modeling, fading, and positive reinforcement enable individuals to develop social engagement skills and begin to progress communicatively in a step-by-step manner. There are many treatment plans that exist and it is recommended for families to do thorough research before deciding on their treatment approach. Self-modeling An affected child is brought into the classroom or the environment where the child will not speak and is videotaped. First, the teacher or another adult prompts the child with questions that likely will not be answered. A parent, or someone the child feels comfortable speaking to, then replaces the prompter and asks the child the same questions, this time eliciting a verbal response. The two videos of the conversations are then edited together to show the child directly answering the questions posed by the teacher or other adult. This video is then shown to the child over a series of several weeks, and every time the child sees themself verbally answering the teacher/other adult, the tape is stopped and the child is given positive reinforcement.Such videos can also be shown to affected childrens classmates to set an expectation in their peers that they can speak. The classmates thereby learn the sound of the childs voice and, albeit through editing, have the opportunity to see the child conversing with the teacher. Mystery motivators Mystery motivation is often paired with self-modeling. An envelope is placed in the childs classroom in a visible place. On the envelope, the childs name is written along with a question mark. Inside is an item that the childs parent has determined to be desirable to the child. The child is told that when they ask for the envelope loudly enough for the teacher and others in the classroom to hear, the child will receive the mystery motivator. The class is also told of the expectation that the child ask for the envelope loudly enough that the class can hear. Stimulus fading Affected subjects can be brought into a controlled environment with someone with whom they are at ease and can communicate. Gradually, another person is introduced into the situation. One example of stimulus fading is the sliding-in technique, where a new person is slowly brought into the talking group. This can take a long time for the first one or two faded-in people but may become faster as the patient gets more comfortable with the technique. As an example, a child may be playing a board game with a family member in a classroom at school. Gradually, the teacher is brought in to play as well. When the child adjusts to the teachers presence, then a peer is brought in to be a part of the game. Each person is only brought in if the child continues to engage verbally and positively. Desensitization The subject communicates indirectly with a person to whom they are afraid to speak through such means as email, instant messaging (text, audio or video), online chat, voice or video recordings, and speaking or whispering to an intermediary in the presence of the target person. This can make the subject more comfortable with the idea of communicating with this person. Shaping The subject is slowly encouraged to speak. The subject is reinforced first for interacting nonverbally, then for saying certain sounds (such as the sound that each letter of the alphabet makes) rather than words, then for whispering, and finally saying a word or more. Spacing Spacing is important to integrate, especially with self-modeling. Repeated and spaced out use of interventions is shown to be the most helpful long-term for learning. Viewing videotapes of self-modeling should be shown over a spaced out period of time of approximately 6 weeks. Drug treatments Some practitioners believe there would be evidence indicating anxiolytics to be helpful in treating children and adults with selective mutism, to decrease anxiety levels and thereby speed the process of therapy. Use of medication may end after nine to twelve months, once the person has learned skills to cope with anxiety and has become more comfortable in social situations. Medication is more often used for older children, teenagers, and adults whose anxiety has led to depression and other problems. Medication, when used, should never be considered the entire treatment for a person with selective mutism. However, the reason why medication needs to be considered as a treatment at all is because selective mutism is still prevalent, despite psychosocial efforts. But while on medication, the person should still be in therapy to help them learn how to handle anxiety and prepare them for life without medication, as medication is typically a short-term solution.Since selective mutism is categorized as an anxiety disorder, using similar medication to treat either makes sense. Antidepressants have been used in addition to self-modeling and mystery motivation to aid in the learning process. Furthermore, SSRIs in particular have been used to treat selective mutism. In a systematic review, ten studies were looked at which involved SSRI medications, and all reported medication was well tolerated. In one of them, Black and Uhde (1994) conducted a double-blind, placebo-controlled study investigating the effects of fluoxetine. By parent report, fluoxetine-treated children showed significantly greater improvement than placebo-treated children. In another, Dummit III et al. (1996) administered fluoxetine to 21 children for nine weeks and found that 76% of the children had reduced or no symptoms by the end of the experiment. This indicates that fluoxetine is an SSRI that is indeed helpful in treating selective mutism. History In 1877, German physician Adolph Kussmaul described children who were able to speak normally but often refused to as having a disorder he named aphasia voluntaria. Although this is now an obsolete term, it was part of an early effort to describe the concept now called selective mutism. In 1980, a study by Torey Hayden identified what she called four "subtypes" of elective mutism (as it was called then), although this set of subtypes is not in current diagnostic use. These subtypes are no longer recognized, though "speech phobia" is sometimes used to describe a selectively mute person who appears not to have any symptoms of social anxiety. The Diagnostic and Statistical Manual of Mental Disorders (DSM), first published in 1952, first included selective mutism in its third edition, published in 1980. Selective mutism was described as "a continuous refusal to speak in almost all social situations" despite normal ability to speak. While "excessive shyness" and other anxiety-related traits were listed as associated features, predisposing factors included "maternal overprotection", "mental retardation", and trauma. Elective mutism in the third edition revised (DSM III-R) is described similarly to the third edition except for specifying that the disorder is not related to social phobia. In 1994, Sue Newman, co-founder of the Selective Mutism Foundation, requested that the fourth edition of the DSM reflect the name change from elective mutism to selective mutism and describe the disorder as a failure to speak. The relation to anxiety disorders was emphasized, particularly in the revised version (DSM IV-TR). As part of the reorganization of the DSM categories, the DSM-5 moved selective mutism from the section "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence" to the section for anxiety disorders. See also June and Jennifer Gibbons, the Silent Twins Citations == Further reading ==

Sickle cell trait

Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene (is heterozygous), but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele (is homozygous). Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin (the two alleles are codominant with respect to the actual concentration of hemoglobin in the circulating cells). Sickle cell disease is a blood disorder wherein there is a single amino acid substitution in the hemoglobin protein of the red blood cells, which causes these cells to assume a sickle shape, especially when under low oxygen tension. Sickling and sickle cell disease also confer some resistance to malaria parasitization of red blood cells, so that individuals with sickle-cell trait (heterozygotes) have a selective advantage in environments where malaria is present. Symptoms and signs Sickle cell trait is a hemoglobin genotype AS and is generally regarded as a benign condition. However, individuals with sickle cell trait may have rare complications. For example, in November 2010, Dr. Jeffery K. Taubenberger of the National Institutes of Health discovered the earliest proof of sickle-cell disease while looking for the virus of the 1918 flu during the autopsy of an African-American soldier. Taubenbergers autopsy results showed that the soldier had had a sickle-cell crisis that contributed to his death even though he had only one copy of the gene. There have been calls to reclassify sickle cell trait as a disease state, based on its malignant clinical presentations. Significance may be greater during exercise. Association with other medical conditions Malaria The sickle cell trait provides a survival advantage against malaria fatality over people with normal hemoglobin in regions where malaria is endemic. The trait is known to cause significantly fewer deaths due to malaria, especially when Plasmodium falciparum is the causative organism. This is a prime example of natural selection, evidenced by the fact that the geographical distribution of the gene for hemoglobin S and the distribution of malaria in Africa virtually overlap. Because of the unique survival advantage, people with the trait become increasingly numerous as the number of malaria-infected people increases. Conversely, people who have normal hemoglobin tend to succumb to the complications of malaria.The way in which sickle cell protects against malaria is attributed to several different things. One of the more common explanations is that the sickle hemoglobin inhibits the plasmodium parasite from infecting the red blood cells which reduces the number of malaria parasites to infect the host. Another factor is the production of heme oxygenase-1 (HO-1) enzyme, which is highly present in the sickle hemoglobin. This enzyme produces carbon monoxide which has been proven to protect against cerebral malaria. Established associations Hematuria Hyposthenuria Renal medullary carcinoma, a cancer affecting the kidney, is a very rare complication seen in patients with sickle cell trait. Renal papillary necrosis (only considered "possible" by some sources) Splenic infarcts at high altitude. Surgery may not always be necessary. Sudden deaths during physical exertion in African-American US army recruits, and athletes Urinary tract infection Suggested Probable: complicated hyphema, venous thromboembolic events, fetal loss, neonatal deaths, and preeclampsia Possible: acute chest syndrome, asymptomatic bacteriuria, and anemia in pregnancy Insufficient evidence: retinopathy, cholelithiasis, priapism, leg ulcers, liver necrosis, avascular necrosis of the femoral head, and stroke. An association with complicated migraines has been suggested.There have been reports of pulmonary venous thromboembolism in pregnant women with sickle cell trait, or men during prolonged airflight, and mild strokes and abnormalities on PET scans in children with the trait.Sickle cell trait appears to worsen the complications seen in diabetes mellitus type 2 (retinopathy, nephropathy and proteinuria) and provoke hyperosmolar diabetic coma nephropathy, especially in male patients. Genetics Normally, a person inherits two copies of the gene that produces beta-globin, a protein needed to produce normal hemoglobin (hemoglobin A, genotype AA). A person with sickle cell trait inherits one normal allele and one abnormal allele encoding hemoglobin S (hemoglobin genotype AS).The sickle cell trait can be used to demonstrate the concepts of co-dominance and incomplete dominance. An individual with the sickle cell trait shows incomplete dominance when the shape of the red blood cell is considered. This is because the sickling happens only at low oxygen concentrations. With regards to the actual concentration of hemoglobin in the circulating cells, the alleles demonstrate co-dominance as both normal and mutant forms co-exist in the bloodstream. Thus it is an ambiguous condition showing both incomplete dominance and co-dominance.Unlike the sickle-cell trait, sickle-cell disease is passed on in a recessive manner. Sickle cell anemia affects about 72,000 people in the United States. Most Americans who have sickle cell anemia are of African descent. The disease also affects Americans from the Caribbean, Central America, and parts of South America, Turkey, Greece, Italy, the Middle East and East India. Sickle-cell disease and the associated trait are most prevalent in Africa and Central America, which is attributed to natural selection: the sickle-cell trait confers a survival advantage in areas with a high occurrence of malaria, which has a high death rate among individuals without the trait.There also have been studies that show changes in the globin genes. There have been noted changes in the beta-globin sequence, to what is known as the sickle hemoglobin. The significance of the sickle-cell trait is that it does not show any symptoms, nor does it cause any major difference in blood cell count. The trait confers about 30% protection against malaria and its occurrence appears to have risen tremendously in Africa, India and the Middle East. Some findings also show the reduction of the sickle-cell trait in those who retain much more fetal hemoglobin than usual in adulthood. Fetal hemoglobin likely plays a role in the prevention of sickling. Elevated fetal hemoglobin levels have been observed in populations where sickle-cell disease is prevalent. Whole genome sequence analysis has identified a single origin of the sickle trait, with one haplotype ancestral to all sickle-cell variants. This haplotype is thought to have originated in the Sahara during the Holocene Wet Phase around 7,300 years ago. Sickle cell variants descended from this ancestral haplotype comprise five haplotypes named after toponyms or ethnolinguistic groups (the Arabian/Indian, Benin, Cameroon, Central African Republic/Bantu, and Senegal variants), and another designation earmarked for atypical sickle-cell haplotypes. Their clinical importance is because some are associated with higher HbF levels (e.g., Senegal and Saudi-Asian variants tend to have milder disease). In athletes In some cases, athletes with sickle cell trait do not achieve the same level of performance as elite athletes with normal hemoglobin (AA). Athletes with sickle cell trait and their instructors must be aware of the dangers of the condition during anaerobic exertion especially in hot and dehydrated conditions. In rare cases, exercise-induced dehydration or exhaustion may cause healthy red blood cells to turn sickle-shaped, which can cause death during sporting activities.While more research is necessary on the topic, the correlation found between individuals with sickle cell trait and an increased risk of sudden death appears to be related to microcirculatory disorders, during exercise. In recent years the NCAA has partnered with the ACSM and issued a joint statement, warning athletes about both the prevalence and the potential risk factors of sickle cell trait. The NCAA has also recently encouraged athletes to become aware of their sickle cell trait status, as the trait itself does not typically result in symptoms under normal conditions but can become dangerous during extreme physical activity similar to the daily training that athletes undergo.Normal hemoglobin (and hemoglobin S in the presence of oxygen) contains a deformability characteristic that allows erythrocytes to essentially squeeze their way into smaller vessels, including those involved in microcirculation to the capillaries within muscle tissue as well as blood supply embedded within organ tissues. When hemoglobin S is deprived of oxygen, it can polymerize, which is what is proposed to cause the "sickled" cells. The sickled erythrocytes present a decreased deformability when compared to normal erythrocytes, leading to distress in circulation into the smaller vessels involved in microcirculation, particularly, in this case, the capillaries embedded in muscle tissue.The resulting microvasculatory distress in capillaries specific to muscle tissue can cause acute rhabdomyolysis and necrosis within the muscle cells. The inflammation and leakage of intracellular material resulting from muscle cell necrosis releases a particular protein, myoglobin, into the blood stream. While necessary in muscle tissue to bind iron and oxygen, myoglobin circulating through the bloodstream can break down into smaller compounds that damage kidney cells, leading to various complications, such as those seen in sickle cell trait athletes during high levels of physical exertion.Because of the link between deformability and sickled cells, deformability can be used to evaluate the amount of sickled cells in the blood. Deformability of the erythrocytes that cause the microcirculatory distress can be demonstrated through various other hemorheological characteristics. In order to determine the deformability of erythrocytes multiple factors including blood and plasma viscosity and hematocrit (a calculation of the percent of red blood cells present in the blood) are measured. Alpha-thalassemia Alpha-thalassemia, like sickle cell trait, is typically inherited in areas with increased exposure to malaria. It manifests itself as a decreased expression of alpha-globin chains, causing an imbalance and excess of beta-globin chains, and can occasionally result in anemic symptoms. The abnormal hemoglobin can cause the body to destroy red blood cells, essentially causing anemia.In endurance-trained individuals with sickle cell trait the presence of alpha-thalassemia has been shown to act protectively against microvasculatory distress before, during, and after exercise. Signs, symptoms, and prevention Because of the microcirculatory distress, a telltale sign or symptom of a potential sickling collapse is cramping. Specifically to sickle cell trait, cramping occurs in the lower extremities and back in athletes undergoing intense physical activity or exertion. In comparison to heat cramps, sickling cramps are less intense in terms of pain and have a weakness and fatigue associated with them, as opposed to tightly contracted muscles that lock up during heat cramps.A sickling collapse comes on slowly, following cramps, weakness, general body aches and fatigue. Individuals with known positive sickle cell trait status experiencing significant muscle weakness or fatigue during exercise should take extra time to recover and hydrate before returning to activity in order to prevent further symptoms.A collapse can be prevented by taking steps to ensure sufficient oxygen levels in the blood. Among these preventative measures are proper hydration and gradual acclimation to conditions such as heat, humidity, and decreased air pressure due to higher altitude. Gradual progression of exertion levels also helps athletes bodies adjust and compensate, gaining fitness slowly over the course of several weeks. See also Ryan Clark (American football) References == External links ==

Mydriasis

Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. Normally, as part of the pupillary light reflex, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day. A mydriatic pupil will remain excessively large even in a bright environment. The excitation of the radial fibres of the iris which increases the pupillary aperture is referred to as a mydriasis. More generally, mydriasis also refers to the natural dilation of pupils, for instance in low light conditions or under sympathetic stimulation. Fixed, unilateral mydriasis could be a symptom of raised intracranial pressure. The opposite, constriction of the pupil, is referred to as miosis. Both mydriasis and miosis can be physiological. Anisocoria is the condition of one pupil being more dilated than the other. Causes There are two types of muscle that control the size of the iris: the iris sphincter, composed of circularly arranged muscle fibers, and the iris dilator, composed of radially arranged muscle fibers. The sphincter is controlled by nerves of the parasympathetic nervous system, and the dilator by the sympathetic nervous system. Sympathetic stimulation of the adrenergic receptors causes the contraction of the radial muscle and subsequent dilation of the pupil. Conversely, parasympathetic stimulation causes contraction of the circular muscle and constriction of the pupil. The mechanism of mydriasis depends on the agent being used. It usually involves either a disruption of the parasympathetic nerve supply to the eye (which normally constricts the pupil) or overactivity of the sympathetic nervous system (SNS). Pupil diameter also increases in reaction to cognitive tasks requiring memory and attention, and this phenomenon is used as an indicator of mental activation (‘arousal’) in psychophysiological experiments. Drugs A mydriatic is an agent that induces dilation of the pupil. Drugs such as tropicamide are used in medicine to permit examination of the retina and other deep structures of the eye, and also to reduce painful ciliary muscle spasm (see cycloplegia). One effect of administration of a mydriatic is intolerance to bright light (photophobia). Purposefully-induced mydriasis via mydriatics is also used as a diagnostic test for Horners syndrome. Mydriasis can be induced via modulation of adrenergic or cholinergic signalling. Drugs that can cause mydriasis include: Stimulants (typically monoaminergics) such as amphetamines, cocaine, MDMA, and mephedrone. Anticholinergics such as diphenhydramine, atropine, hyoscyamine, and scopolamine antagonize the muscarinic acetylcholine receptors in the eye. Blocking acetylcholine receptors reduces the pupillary muscles ability to constrict and causes dilation (which is critical in eye surgery procedures such as cataract surgery which require uninterrupted access to the inner eye via the pupillary aperture, thus requiring that the eye be both paralyzed and anesthetized before the procedure can go ahead). The antimuscarinic, tropicamide, may be used as a mydriastic agent during surgery. Serotonergics such as LSD, psilocybin mushrooms, mescaline and 2C-B. These drugs are typically hallucinogens. Similarly, selective serotonin reuptake inhibitors can cause mydriasis. Dissociatives such as dextromethorphan (an SSRI and sigma-1 agonist). Certain GABAergic drugs, such as phenibut and GHB. Adrenergic agonists, such as phenylephrine and cyclomydril. Adrenergic agonists may be used if strong mydriasis is needed in surgery. Norepinephrine is a hormone and neurotransmitter that regulates the involuntary muscles of the autonomic nervous system, including dilation of the pupil aperture via the muscles of the iris. Hence adrenergic agonists mimic the activity of norepinephrine, which is how they induce mydriasis.Natural release of the hormone oxytocin can cause mild to moderate mydriasis.Long term effects of drugs can also cause mydriasis, for example opioid withdrawal. Autonomic neuropathy Parasympathetic fibers travel with cranial nerve III, the oculomotor nerve, to innervate the circular layer of muscle of the eye (sphincter pupillae). Damage to this nerve typically manifests itself as mydriasis, because the sympathetic supply to the pupil, which causes mydriasis, remains unaffected, and therefore unopposed. Multiple central nervous system disorders e.g. epilepsy, stroke, and impending brain herniation are known to lead to temporal mydriasis as well. A brain catastrophe, or a rapidly increasing brain mass, can cause compression of the oculomotor nerve. Trauma In cases of head injury or orbit trauma (eye injury), the iris sphincter (the muscle responsible for closing the pupil) or the nerves controlling it can be damaged, reducing or eliminating the normal pupillary light reflex. References == External links ==

Hurler–Scheie syndrome

Hurler–Scheie syndrome is a genetic disorder caused by the buildup of glycosaminoglycans (GAGs) in various organ tissues. It is a cutaneous condition, also characterized by mild mental retardation and corneal clouding. Respiratory problems, sleep apnea, and heart disease may develop in adolescence.Hurler–Scheie syndrome is classified as a lysosomal storage disease. Patients with Hurler–Scheie syndrome lack the ability to break down GAGs in their lysosomes due a deficiency of the enzyme iduronidase. All forms of mucopolysaccharidosis type I (MPS I) are a spectrum of the same disease. Hurler-Sheie is the subtype of MPS I with intermediate severity. Hurler syndrome is the most severe form, while Scheie syndrome is the least severe form. Some clinicians consider the differences between Hurler, Hurler-Scheie, and Scheie syndromes to be arbitrary. Instead, they classify these patients as having "severe", "intermediate", or "attenuated" MPS I. See also Mucopolysaccharidosis References == External links ==

Rabies

Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, violent movements, uncontrolled excitement, fear of water, an inability to move parts of the body, confusion, and loss of consciousness. Once symptoms appear, the result is virtually always death, regardless of treatment. The time period between contracting the disease and the start of symptoms is usually one to three months but can vary from less than one week to more than one year. The time depends on the distance the virus must travel along peripheral nerves to reach the central nervous system.Rabies is caused by lyssaviruses, including the rabies virus and Australian bat lyssavirus. It is spread when an infected animal bites or scratches a human or other animals. Saliva from an infected animal can also transmit rabies if the saliva comes into contact with the eyes, mouth, or nose. Globally, dogs are the most common animal involved. In countries where dogs commonly have the disease, more than 99% of rabies cases are the direct result of dog bites. In the Americas, bat bites are the most common source of rabies infections in humans, and less than 5% of cases are from dogs. Rodents are very rarely infected with rabies. The disease can be diagnosed only after the start of symptoms.Animal control and vaccination programs have decreased the risk of rabies from dogs in a number of regions of the world. Immunizing people before they are exposed is recommended for those at high risk, including those who work with bats or who spend prolonged periods in areas of the world where rabies is common. In people who have been exposed to rabies, the rabies vaccine and sometimes rabies immunoglobulin are effective in preventing the disease if the person receives the treatment before the start of rabies symptoms. Washing bites and scratches for 15 minutes with soap and water, povidone-iodine, or detergent may reduce the number of viral particles and may be somewhat effective at preventing transmission. As of 2016, only fourteen people were documented to have survived a rabies infection after showing symptoms. However, research conducted in 2010 among a population of people in Perú with a self-reported history of one or more bites from vampire bats (commonly infected with rabies), found that out of 73 individuals reporting previous bat bites, 7 people had rabies virus-neutralizing antibodies (rVNA). Since only one member of this group reported prior vaccination for rabies, the findings of the research suggest previously undocumented cases of infection and viral replication followed by an abortive infection. This could indicate that in rare cases people may have an exposure to the virus without treatment and develop natural antibodies as a result. Rabies causes about 59,000 deaths worldwide per year, about 40% of which are in children under the age of 15. More than 95% of human deaths from rabies occur in Africa and Asia.Rabies is present in more than 150 countries and on all continents but Antarctica. More than 3 billion people live in regions of the world where rabies occurs. A number of countries, including Australia and Japan, as well as much of Western Europe, do not have rabies among dogs. Many Pacific islands do not have rabies at all. It is classified as a neglected tropical disease. Etymology The name rabies is derived from the Latin rabies, "madness". This, in turn, may be related to the Sanskrit rabhas, "to rage". The Greeks derived the word lyssa, from lud or "violent"; this root is used in the genus name of the rabies virus, Lyssavirus. Signs and symptoms The period between infection and the first symptoms (incubation period) is typically 1–3 months in humans. This period may be as short as four days or longer than six years, depending on the location and severity of the wound and the amount of virus introduced. Initial symptoms of rabies are often nonspecific such as fever and headache. As rabies progresses and causes inflammation of the brain and meninges, symptoms can include slight or partial paralysis, anxiety, insomnia, confusion, agitation, abnormal behavior, paranoia, terror, and hallucinations. The person may also have fear of water.The symptoms eventually progress to delirium, and coma. Death usually occurs 2 to 10 days after first symptoms. Survival is almost unknown once symptoms have presented, even with intensive care.Rabies has also occasionally been referred to as hydrophobia ("fear of water") throughout its history. It refers to a set of symptoms in the later stages of an infection in which the person has difficulty swallowing, shows panic when presented with liquids to drink, and cannot quench their thirst. Any mammal infected with the virus may demonstrate hydrophobia. Saliva production is greatly increased, and attempts to drink, or even the intention or suggestion of drinking, may cause excruciatingly painful spasms of the muscles in the throat and larynx. Since the infected individual cannot swallow saliva and water, the virus has a much higher chance of being transmitted, because it multiplies and accumulates in the salivary glands and is transmitted through biting. Hydrophobia is commonly associated with furious rabies, which affects 80% of rabies-infected people. The remaining 20% may experience a paralytic form of rabies that is marked by muscle weakness, loss of sensation, and paralysis; this form of rabies does not usually cause fear of water. Cause Rabies is caused by a number of lyssaviruses including the rabies virus and Australian bat lyssavirus. Duvenhage lyssavirus may cause a rabies-like infection.The rabies virus is the type species of the Lyssavirus genus, in the family Rhabdoviridae, order Mononegavirales. Lyssavirions have helical symmetry, with a length of about 180 nm and a cross-section of about 75 nm. These virions are enveloped and have a single-stranded RNA genome with negative sense. The genetic information is packed as a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA genome of the virus encodes five genes whose order is highly conserved: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L).To enter cells, trimeric spikes on the exterior of the membrane of the virus interact with a specific cell receptor, the most likely one being the acetylcholine receptor. The cellular membrane pinches in a procession known as pinocytosis and allows entry of the virus into the cell by way of an endosome. The virus then uses the acidic environment, which is necessary, of that endosome and binds to its membrane simultaneously, releasing its five proteins and single-strand RNA into the cytoplasm.Once within a muscle or nerve cell, the virus undergoes replication. The L protein then transcribes five mRNA strands and a positive strand of RNA all from the original negative strand RNA using free nucleotides in the cytoplasm. These five mRNA strands are then translated into their corresponding proteins (P, L, N, G and M proteins) at free ribosomes in the cytoplasm. Some proteins require post-translative modifications. For example, the G protein travels through the rough endoplasmic reticulum, where it undergoes further folding, and is then transported to the Golgi apparatus, where a sugar group is added to it (glycosylation).When there are enough viral proteins, the viral polymerase will begin to synthesize new negative strands of RNA from the template of the positive-strand RNA. These negative strands will then form complexes with the N, P, L and M proteins and then travel to the inner membrane of the cell, where a G protein has embedded itself in the membrane. The G protein then coils around the N-P-L-M complex of proteins taking some of the host cell membrane with it, which will form the new outer envelope of the virus particle. The virus then buds from the cell.From the point of entry, the virus is neurotropic, traveling along the neural pathways into the central nervous system. The virus usually first infects muscle cells close to the site of infection, where they are able to replicate without being noticed by the hosts immune system. Once enough virus has been replicated, they begin to bind to acetylcholine receptors at the neuromuscular junction. The virus then travels through the nerve cell axon via retrograde transport, as its P protein interacts with dynein, a protein present in the cytoplasm of nerve cells. Once the virus reaches the cell body it travels rapidly to the central nervous system (CNS), replicating in motor neurons and eventually reaching the brain. After the brain is infected, the virus travels centrifugally to the peripheral and autonomic nervous systems, eventually migrating to the salivary glands, where it is ready to be transmitted to the next host.: 317 Transmission All warm-blooded species, including humans, may become infected with the rabies virus and develop symptoms. Birds were first artificially infected with rabies in 1884; however, infected birds are largely, if not wholly, asymptomatic, and recover. Other bird species have been known to develop rabies antibodies, a sign of infection, after feeding on rabies-infected mammals.The virus has also adapted to grow in cells of cold-blooded vertebrates. Most animals can be infected by the virus and can transmit the disease to humans. Worldwide, about 99% of human rabies cases come from domestic dogs. Other sources of rabies in humans include bats, monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, cats, and mongooses (normally either the small Asian mongoose or the yellow mongoose).Rabies may also spread through exposure to infected bears, domestic farm animals, groundhogs, weasels, and other wild carnivorans. However, lagomorphs, such as hares and rabbits, and small rodents, such as chipmunks, gerbils, guinea pigs, hamsters, mice, rats, and squirrels, are almost never found to be infected with rabies and are not known to transmit rabies to humans. Bites from mice, rats, or squirrels rarely require rabies prevention because these rodents are typically killed by any encounter with a larger, rabid animal, and would, therefore, not be carriers. The Virginia opossum (a marsupial, unlike the other mammals named in this paragraph, which are all eutherians/placental), has a lower internal body temperature than the rabies virus prefers and therefore is resistant but not immune to rabies. Marsupials, along with monotremes (platypuses and echidnas), typically have lower body temperatures than similarly sized eutherians.The virus is usually present in the nerves and saliva of a symptomatic rabid animal. The route of infection is usually, but not always, by a bite. In many cases, the infected animal is exceptionally aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior. This is an example of a viral pathogen modifying the behavior of its host to facilitate its transmission to other hosts. After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels retrograde along the efferent nerves toward the central nervous system. During this phase, the virus cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to prevent symptomatic rabies. When the virus reaches the brain, it rapidly causes encephalitis, the prodromal phase, which is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord, producing transverse myelitis.Although it is theoretically possible for rabies-infected humans to transmit it to others by biting or otherwise, no such cases have ever been documented, because infected humans are usually hospitalized and necessary precautions taken. Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue (urine, blood, feces), does not constitute an exposure and does not require post-exposure prophylaxis. But as the virus is present in sperm and vaginal secretions, it might be possible for rabies to spread through sex. There are only a handful of recorded cases of human-to-human transmission of rabies, and all occurred through organ transplants from infected donors. Diagnosis Rabies can be difficult to diagnose because, in the early stages, it is easily confused with other diseases or even with a simple aggressive temperament. The reference method for diagnosing rabies is the fluorescent antibody test (FAT), an immunohistochemistry procedure, which is recommended by the World Health Organization (WHO). The FAT relies on the ability of a detector molecule (usually fluorescein isothiocyanate) coupled with a rabies-specific antibody, forming a conjugate, to bind to and allow the visualisation of rabies antigen using fluorescent microscopy techniques. Microscopic analysis of samples is the only direct method that allows for the identification of rabies virus-specific antigen in a short time and at a reduced cost, irrespective of geographical origin and status of the host. It has to be regarded as the first step in diagnostic procedures for all laboratories. Autolysed samples can, however, reduce the sensitivity and specificity of the FAT. The RT PCR assays proved to be a sensitive and specific tool for routine diagnostic purposes, particularly in decomposed samples or archival specimens. The diagnosis can be reliably made from brain samples taken after death. The diagnosis can also be made from saliva, urine, and cerebrospinal fluid samples, but this is not as sensitive or reliable as brain samples. Cerebral inclusion bodies called Negri bodies are 100% diagnostic for rabies infection but are found in only about 80% of cases. If possible, the animal from which the bite was received should also be examined for rabies.Some light microscopy techniques may also be used to diagnose rabies at a tenth of the cost of traditional fluorescence microscopy techniques, allowing identification of the disease in less-developed countries. A test for rabies, known as LN34, is easier to run on a dead animals brain and might help determine who does and does not need post-exposure prevention. The test was developed by the CDC in 2018.The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis, in particular infection with viruses such as herpesviruses, enteroviruses, and arboviruses such as West Nile virus. The most important viruses to rule out are herpes simplex virus type one, varicella zoster virus, and (less commonly) enteroviruses, including coxsackieviruses, echoviruses, polioviruses, and human enteroviruses 68 to 71.New causes of viral encephalitis are also possible, as was evidenced by the 1999 outbreak in Malaysia of 300 cases of encephalitis with a mortality rate of 40% caused by Nipah virus, a newly recognized paramyxovirus. Likewise, well-known viruses may be introduced into new locales, as is illustrated by the outbreak of encephalitis due to West Nile virus in the eastern United States. Prevention Almost all human exposure to rabies was fatal until a vaccine was developed in 1885 by Louis Pasteur and Émile Roux. Their original vaccine was harvested from infected rabbits, from which the virus in the nerve tissue was weakened by allowing it to dry for five to ten days. Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines. The human diploid cell rabies vaccine was started in 1967. Less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available. A recombinant vaccine called V-RG has been used in Belgium, France, Germany, and the United States to prevent outbreaks of rabies in undomesticated animals. Immunization before exposure has been used in both human and nonhuman populations, where, as in many jurisdictions, domesticated animals are required to be vaccinated. The Missouri Department of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states the following can help reduce the risk of contracting rabies:Vaccinating dogs, cats, and ferrets against rabies Keeping pets under supervision Not handling wild animals or strays Contacting an animal control officer upon observing a wild animal or a stray, especially if the animal is acting strangely If bitten by an animal, washing the wound with soap and water for 10 to 15 minutes and contacting a healthcare provider to determine if post-exposure prophylaxis is required28 September is World Rabies Day, which promotes the information, prevention, and elimination of the disease.In Asia and in parts of the Americas and Africa, dogs remain the principal host. Mandatory vaccination of animals is less effective in rural areas. Especially in developing countries, pets may not be privately kept and their destruction may be unacceptable. Oral vaccines can be safely distributed in baits, a practice that has successfully reduced rabies in rural areas of Canada, France, and the United States. In Montreal, Quebec, Canada, baits are successfully used on raccoons in the Mount-Royal Park area. Vaccination campaigns may be expensive, but cost-benefit analysis suggests baits may be a cost-effective method of control. In Ontario, a dramatic drop in rabies was recorded when an aerial bait-vaccination campaign was launched.The number of recorded human deaths from rabies in the United States has dropped from 100 or more annually in the early 20th century to one or two per year due to widespread vaccination of domestic dogs and cats and the development of human vaccines and immunoglobulin treatments. Most deaths now result from bat bites, which may go unnoticed by the victim and hence untreated. Treatment After exposure Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given early, and still has a chance of success if delivery is delayed. Every year, more than 15 million people get vaccinated after potential exposure. While this works well, the cost is significant. In the US it is recommended people receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period. HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars. In the UK, one dose of HRIG costs the National Health Service £1,000, although this is not flagged as a "high-cost medication". A full course of vaccine costs £120–180. As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site.People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3. The side effects of modern cell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive. It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens. In children less than a year old, the lateral thigh is recommended. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles. Povidone-iodine or alcohol is then recommended to reduce the virus further.Awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person, is an indication for post-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on a cost–benefit analysis. However, a 2002 study has supported the protocol of precautionary administration of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur with the victim being unaware. After onset At least two treatment schemes have been proposed for treating rabies after the onset of symptoms, the Milwaukee Protocol and the Recife Protocol. The Milwaukee Protocol was first used in 2004 on Jeanna Giese, who became the first person known to have survived rabies without preventive treatments before symptom onset. The protocol puts a person into a chemically induced coma and uses antiviral medications to prevent fatal dysautonomia. The overall protocol is complex; the sixth version of the protocol last updated in 2018 consists of 17 pages with 22 steps of treatment, detailed monitoring, and a timeline of expected complications. The Recife Protocol follows the same principle but differs in details like termination of sedation and supplementary medication. Prognosis Vaccination after exposure, PEP, is highly successful in preventing rabies. In unvaccinated humans, rabies is virtually always fatal after neurological symptoms have developed. Epidemiology In 2010, an estimated 26,000 people died from rabies, down from 54,000 in 1990. The majority of the deaths occurred in Asia and Africa. As of 2015, India, followed by China (approximately 6,000) and the Democratic Republic of the Congo (5,600), had the most cases. A 2015 collaboration between the World Health Organization, World Organization of Animal Health (OIE), Food and Agriculture Organization of the United Nation (FAO), and Global Alliance for Rabies Control has a goal of eliminating deaths from rabies by 2030. India India has the highest rate of human rabies in the world, primarily because of stray dogs, whose number has greatly increased since a 2001 law forbade the killing of dogs. Effective control and treatment of rabies in India is hindered by a form of mass hysteria known as puppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help from faith healers rather than medical services. An estimated 20,000 people die every year from rabies in India, more than a third of the global total. Australia Australia has an official rabies-free status, although Australian bat lyssavirus (ABLV), discovered in 1996, is a strain of rabies prevalent in Australian native bat populations. United States Canine-specific rabies has been eradicated in the United States. But rabies is common among wild animals in the United States, and an average of 100 dogs become infected from other wildlife each year.Due to high public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of postexposure prophylaxis, incidence of rabies in humans is very rare in the United States. From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. The most recent rabies death in the United States was an Illinois man who refused treatment after waking up in the night with a bat on his neck; the man died a month later. Occurring in 2021, it was the first case of human rabies in the United States in nearly three years. Europe Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe.In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with live attenuated vaccine in the Swiss Alps. The foxes of Switzerland, proven to be the main source of rabies in the country, ate the chicken heads and immunized themselves.Italy, after being declared rabies-free from 1997 to 2008, has witnessed a reemergence of the disease in wild animals in the Triveneto regions (Trentino-Alto Adige/Südtirol, Veneto and Friuli-Venezia Giulia), due to the spreading of an epidemic in the Balkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011.The United Kingdom has been free of rabies since the early 20th century except for a rabies-like virus (EBLV-2) in a few Daubentons bats. There has been one fatal case of EBLV-2 transmission to a human. There have been four deaths from rabies, transmitted abroad by dog bites, since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902.Sweden and mainland Norway have been free of rabies since 1886. Bat rabies antibodies (but not the virus) have been found in bats. On Svalbard, animals can cross the arctic ice from Greenland or Russia. Mexico Mexico was certified by the World Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years. History Rabies has been known since around 2000 BC. The first written record of rabies is in the Mesopotamian Codex of Eshnunna (c. 1930 BC), which dictates that the owner of a dog showing symptoms of rabies should take preventive measures against bites. If another person were bitten by a rabid dog and later died, the owner was heavily fined.In Ancient Greece, rabies was supposed to be caused by Lyssa, the spirit of mad rage.Ineffective folk remedies abounded in the medical literature of the ancient world. The physician Scribonius Largus prescribed a poultice of cloth and hyena skin; Antaeus recommended a preparation made from the skull of a hanged man.Rabies appears to have originated in the Old World, the first epizootic in the New World occurring in Boston in 1768.Rabies was considered a scourge for its prevalence in the 19th century. In France and Belgium, where Saint Hubert was venerated, the "St Huberts Key" was heated and applied to cauterize the wound. By an application of magical thinking, dogs were branded with the key in hopes of protecting them from rabies. It was not uncommon for a person bitten by a dog merely suspected of being rabid to commit suicide or to be killed by others.In ancient times the attachment of the tongue (the lingual frenulum, a mucous membrane) was cut and removed as this was where rabies was thought to originate. This practice ceased with the discovery of the actual cause of rabies. Louis Pasteurs 1885 nerve tissue vaccine was successful, and was progressively improved to reduce often severe side-effects.In modern times, the fear of rabies has not diminished, and the disease and its symptoms, particularly agitation, have served as an inspiration for several works of zombie or similarly themed fiction, often portraying rabies as having mutated into a stronger virus which fills humans with murderous rage or incurable illness, bringing about a devastating, widespread pandemic. Other animals Rabies is infectious to mammals; three stages of central nervous system infection are recognized. The first stage is a one- to three-day period characterized by behavioral changes and is known as the prodromal stage. The second is the excitative stage, which lasts three to four days. This stage is often known as "furious rabies" for the tendency of the affected animal to be hyper-reactive to external stimuli and bite at anything near. The third is the paralytic stage and is caused by damage to motor neurons. Incoordination is seen, owing to rear limb paralysis, and drooling and difficulty swallowing is caused by paralysis of facial and throat muscles. Death is usually caused by respiratory arrest. Research Biotechnological use The outer shell of the rabies virus, stripped of its RNA contents and thus unable to cause disease, may be used as a vector for the delivery of unrelated genetic material in a research setting. It has the advantage over other pseudotyping methods for gene delivery in that the cell targeting (tissue tropism) is more specific for the central nervous system, a difficult-to-reach site, obviating the need for invasive delivery methods. It

Rabies

is also capable of infecting neighboring "upstream" cells, moving from one cell to axons of the next at synapses, and is thus used for retrograde tracing in neuronal circuits. Potential treatment Evidence indicates artificially increasing the permeability of the blood–brain barrier, which normally does not allow most immune cells across, promotes viral clearance. See also Global Alliance for Rabies Control Rabies in Haiti Eradication of infectious diseases Madstone (folklore) References Further reading Pankhurst, Richard. "The history and traditional treatment of rabies in Ethiopia." Medical History 14, no. 4 (1970): 378-389. External links Rabies at Curlie "Rabies". Centers for Disease Control and Prevention. Retrieved 12 August 2012. Virus Pathogen Database and Analysis Resource (ViPR): Rhabdoviridae OIEs Rabies Portal Archived 13 August 2020 at the Wayback Machine Aerophobia and Hydrophobia in Rabies Videos "Rabies virus". NCBI Taxonomy Browser. 11292.

Anterograde amnesia

In neurology, anterograde amnesia is the inability to create new memories after the event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories created prior to the event are lost while new memories can still be created. Both can occur together in the same patient. To a large degree, anterograde amnesia remains a mysterious ailment because the precise mechanism of storing memories is not yet well understood, although it is known that the regions of the brain involved are certain sites in the temporal cortex, especially in the hippocampus and nearby subcortical regions. Signs and symptoms People with anterograde amnesic syndromes may present with widely varying degrees of forgetfulness. Some with severe cases have a combined form of anterograde and retrograde amnesia, sometimes called global amnesia. In the case of drug-induced amnesia, it may be short-lived and patients can recover from it. In the other case, which has been studied extensively since the early 1970s, patients often have permanent damage, although some recovery is possible, depending on the nature of the pathophysiology. Usually, some capacity for learning remains, although it may be very elementary. In cases of pure anterograde amnesia, patients have recollections of events prior to the injury, but cannot recall day-to-day information or new facts presented to them after the injury occurred.In most cases of anterograde amnesia, patients lose declarative memory, or the recollection of facts, but they retain nondeclarative memory, often called procedural memory. For instance, they are able to remember and in some cases learn how to do things such as talking on the phone or riding a bicycle, but they may not remember what they had eaten earlier that day for lunch. One extensively studied anterograde amnesiac patient, codenamed H.M., demonstrated that despite his amnesia preventing him from learning new declarative information, procedural memory consolidation was still possible, albeit severely reduced in power. He, along with other patients with anterograde amnesia, were given the same maze to complete day after day. Despite having no memory of having completed the maze the day before, unconscious practice of completing the same maze over and over reduced the amount of time needed to complete it in subsequent trials. From these results, Corkin et al. concluded despite having no declarative memory (i.e. no conscious memory of completing the maze exists), the patients still had a working procedural memory (learning done unconsciously through practice). This supports the notion that declarative and procedural memory are consolidated in different areas of the brain. In addition, patients have a diminished ability to remember the temporal context in which objects were presented. Certain authors claim the deficit in temporal context memory is more significant than the deficit in semantic learning ability (described below). Causes This disorder is usually acquired in one of four ways: One cause is benzodiazepine drugs such as midazolam, flunitrazepam, lorazepam, temazepam, nitrazepam, triazolam, clonazepam, alprazolam, diazepam, and nimetazepam; all of these are known to have powerful amnesic effects. This has also been recorded in non-benzodiazepine sedatives or "z-drugs" which act on the same set of receptors; such as zolpidem (also known as Ambien), eszopiclone (also known as Lunesta), and zopiclone (also known by brand names Imovane and Zimovane). A second cause is a traumatic brain injury in which damage is usually done to the hippocampus or surrounding cortices. It may also be caused by a PTSD, a shocking event, or an emotional disorder.Illness, though much rarer, can also cause anterograde amnesia if it causes encephalitis, which is the inflammation of brain tissue. There are several types of encephalitis: one such is herpes simplex encephalitis (HSV), which, if left untreated, can lead to neurological deterioration. How HSV gains access to the brain is unknown; the virus shows a distinct predilection for certain parts of the brain. Initially, it is present in the limbic cortices; it may then spread to the adjacent frontal and temporal lobes. Damage to specific areas can result in reduced or eliminated ability to encode new explicit memories, giving rise to anterograde amnesia. Patients with anterograde amnesia may have episodic, semantic, or both types of explicit memory impaired for events after the trauma that caused the amnesia. This suggests that memory consolidation for different types of memory takes place in different regions of the brain. Despite this, current knowledge on human memory is still insufficient to "map out" the wiring of a human brain to discover which parts of which lobe are responsible for the various episodic and semantic knowledge within a persons memory. Amnesia is seen in patients who, for the reason of preventing another more serious disorder, have parts of their brains known to be involved in memory circuits removed, the most notable of which is known as the medial temporal lobe (MTL) memory system, described below. Patients with seizures originating in the MTL may have either side or both structures removed (there is one structure per hemisphere). In addition, patients with tumors who undergo surgery will often sustain damage to these structures, as is described in a case below. Damage to any part of this system, including the hippocampus and surrounding cortices, results in amnesic syndromes. This is why after a stroke people have a chance of developing cognitive deficits that result in anterograde amnesia, since strokes can involve the temporal lobe in the temporal cortex, and the temporal cortex houses the hippocampus. Finally, anterograde amnesia can be the first clinical sign that Alzheimers disease develops in within the brain. Although later the complications can be much more widespread and strongly impair cognitive processes, at the initial stage of Alzheimers the changes observed can be restricted to anterograde amnesia and a mild deficit in retaining newly learnt sequences. This is explained by the fact that the disease is initiated within the medial temporal lobe and first affacts the entorhinal cortex that directly sends and receives information from the hippocampal formation. Alcohol intoxication Anterograde amnesia can also be caused by alcohol intoxication, a phenomenon commonly known as a blackout. Studies show rapid rises in blood alcohol concentration over a short period of time severely impair or in some cases completely block the brains ability to transfer short-term memories created during the period of intoxication to long-term memory for storage and later retrieval. Such rapid rises are caused by drinking large amounts of alcohol in short periods of time, especially on an empty stomach, as the dilution of alcohol by food slows the absorption of alcohol. Alcohol-related anterograde amnesia is directly related to the rate of consumption of alcohol (and is often associated with binge drinking), and not just the total amount of alcohol consumed in a drinking episode. Test subjects have been found not to experience amnesia when drinking slowly, despite being heavily intoxicated by the end of the experiment. When alcohol is consumed at a rapid rate, the point at which most healthy peoples long-term memory creation starts to fail usually occurs at approximately 0.20% BAC, but can be reached as low as 0.14% BAC for infrequent drinkers. The exact duration of these blackout periods is hard to determine, because most people fall asleep before they end. Upon reaching sobriety, usually after waking, long-term memory creation is completely restored.Chronic alcoholism often leads to a thiamine (vitamin B1) deficiency in the brain, causing Korsakoffs syndrome, a neurological disorder which is generally preceded by an acute neurological condition known as Wernickes encephalopathy (WE). The memory impairment that is pathognomonic to Korsakoffs syndrome predominantly affects the declarative memory, leaving non-declarative memory that is often procedural in nature relatively intact. The disproportionate severity in anterograde episodic memory processes in contrast to other cognitive processes is what differentiates Korsakoff syndrome from other conditions such as alcohol-related dementia. Evidence for the preservation of certain memory processes in the presence of severe anterograde episodic memory serve as experimental paradigm to investigate the components of human memory. Pathophysiology The pathophysiology of anterograde amnesic syndromes varies with the extent of damage and the regions of the brain that were damaged. The most well-described regions indicated in this disorder are the medial temporal lobe (MTL), basal forebrain, and fornix. Beyond the details described below, the precise process of how we remember – on a micro scale – remains a mystery. Neuropsychologists and scientists are still not in total agreement over whether forgetting is due to faulty encoding, accelerated forgetting, or faulty retrieval, although a great deal of data seem to point to the encoding hypothesis. In addition, neuroscientists are also in disagreement about the length of time involved in memory consolidation. Though most researchers, including Hasselmo et al., have found the consolidation process is spread out over several hours before transitioning from a fragile to a more permanent state, others, including Brown et al., posit that memory consolidation can take months or even years in a drawn-out process of consolidation and reinforcement. Further research into the length of time of memory consolidation will shed more light on why anterograde amnesia sometimes affects some memories gained after the event(s) that caused the amnesia, but does not affect other such memories. Medial temporal lobe The MTL memory system includes the hippocampal formation (CA fields, dentate gyrus, subicular complex), perirhinal, entorhinal, and parahippocampal cortices. It is known to be important for the storage and processing of declarative memory, which allows for factual recall. It is also known to communicate with the neocortex in the establishment and maintenance of long-term memories, although its known functions are independent of long-term memory. Nondeclarative memory, on the other hand, which allows for the performance of different skills and habits, is not part of the MTL memory system. Most data point to a "division of labor" among the parts of this system, although this is still being debated and is described in detail below.In animal models, researchers have shown monkeys with damage to both the hippocampus and its adjacent cortical regions were more severely impaired in terms of anterograde amnesia than monkeys with damage localized to hippocampal structures. However, conflicting data in another primate study point to the observation that the amount of tissue damaged does not necessarily correlate with the severity of the memory loss. Furthermore, the data do not explain the dichotomy that exists in the MTL memory system between episodic memory and semantic memory (described below).An important finding in amnesic patients with MTL damage is the impairment of memory in all sensory modalities – sound, touch, smell, taste, and sight. This reflects the fact that the MTL is a processor for all of the sensory modalities, and helps store these kind of thoughts into memory. In addition, subjects can often remember how to perform relatively simple tasks immediately (on the order of 10 seconds), but when the task becomes more difficult, even on the same time scale, subjects tend to forget. This demonstrates the difficulty of separating procedural memory tasks from declarative memory; some elements of declarative memory may be used in learning procedural tasks.MTL amnesic patients with localized damage to the hippocampus retain other perceptual abilities, such as the ability to intelligently function in society, to make conversation, to make ones bed, etc. Additionally, anterograde amnesics without combined retrograde disorders (localized damage to the MTL system) have memories prior to the traumatic event. For this reason, the MTL is not the storage place of all memories; other regions in the brain also store memories. The key is the MTL is responsible for the learning of new materials. Other memory systems A limited number of cases have been described in which patients with damage to other parts of the brain acquired anterograde amnesia. Easton and Parker observed damage to either the hippocampus or the surrounding cortices does not seem to result in severe amnesia in primate models. They suggested damage to the hippocampus and surrounding structures alone does not explain the amnesia they saw in patients, or increasing damage does not correlate with the degree of impairment. Furthermore, the data do not explain the dichotomy that exists in the MTL memory system between episodic and semantic memory. To demonstrate their hypothesis, they used a primate model with damage to the basal forebrain. They proposed that the disruption of neurons that project from the basal forebrain to the MTL are responsible for some of the impairment in anterograde amnesia. Easton and Parker also reported MRI scans of patients with severe anterograde amnesia showed damage beyond to cortical areas around the hippocampus and amygdala (a region of brain involved in emotions) and to surrounding white matter (white matter in the brain consists of axons, long projections of neuronal cell bodies). Another case described the onset of anterograde amnesia as a result of cell death in the fornix, another structure that carries information from the hippocampus to the structures of the limbic system and the diencephalon. The patient in this case did not show any disconnection syndrome, which is unexpected since the structures involved divide the brain hemispheres (both sides of her brain were able to communicate). Instead, she showed signs of amnesia. The final diagnosis was made by MRI. This particular amnesic syndrome is difficult to diagnose and often is misdiagnosed by physicians as an acute psychiatric disorder. Reorganization of memory When there is damage to just one side of the MTL, there is opportunity for normal functioning or near-normal function for memories. Neuroplasticity describes the ability of the cortex to remap when necessary. Remapping can occur in cases like the one above and with time the patient can recover and become more skilled at memory retention. A case report describing a patient who had two lobectomies – in the first, doctors removed part of her right MTL first because of seizures originating from the region, and later her left because she developed a tumor – demonstrates this. This case is unique because it is the only one in which both sides of the MTL were removed at different times. The authors observed that the patient was able to recover some ability to learn when she had only one MTL, but observed the deterioration of function when both sides of the MTL were affected. The reorganization of brain function for epileptic patients has had limited investigation, but imaging results show that it may occur. Rehabilitation Approaches used to treat those with anterograde amnesia often use interventions which focus on compensatory techniques, such as beepers, written notes, diaries or through intensive training programs involving the active participation of the individual concerned, along with their supporting network of family and friends. In this perspective, environmental adaptation techniques are used, such as the compensatory technique education to training (exercise), organizational strategies, visual imagery and verbal labeling. In addition, other techniques are also used in rehabilitation, such as implicit tasks, speech and mnemotechnic methods. So far, it has been proven that education techniques of compensatory strategies for memory disorders are effective in individuals with minor traumatic brain injuries. In moderately or severely injured individuals, effective interventions are those appealing to external aids, such as reminders in order to facilitate particular knowledge or skill acquisition. Reality orientation techniques are also considered; their purpose is to enhance orientation using stimulation and repetition of the basic orientation information. These techniques are regularly applied in populations of patients primarily presenting with dementia and head injuries. Controversies Episodic versus semantic memory As described above, patients with anterograde amnesia have a wide range of forgetfulness. Declarative memory can be further subdivided into episodic and semantic memory. Episodic memory is the recollection of autobiographical information with a temporal and/or spatial context, whereas semantic memory involves recall of factual information with no such association (language, history, geography, etc.). In a case study of a girl who developed anterograde amnesia during childhood, it was determined that the patient ("C.L.") retained semantic memory while having an extreme impairment of episodic memory.One patient, known by the codename "Gene", was involved in a motorcycle accident that damaged significant portions of his frontal and temporal lobes, including his left hippocampus. As a result, he cannot remember any specific episode in his life, such as a train derailment near his house. However, his semantic memory is intact; he remembers that he owns a car and two motorcycles, and he can even remember the names of his classmates in a school photograph. In stark contrast, a woman whose temporal lobes were damaged in the front due to encephalitis lost her semantic memory; she lost her memory of many simple words, historical events, and other trivial information categorized under semantic memory. However, her episodic memory was left intact; she can recall episodes such as her wedding and her fathers death with great detail. Vicari et al. describe that it remains unclear whether neural circuits involved in semantic and episodic memory overlap partially or completely, and this case seems to suggest that the two systems are independent. Both of the patients hippocampal and diencephalic structures on the right and left sides were disconnected. When C.L. came to Vicari et al.s office, her chief complaint was forgetfulness involving both semantic and episodic memory. After administering a battery of neuropsychological tests, Vicari determined that C.L. performed well in tests of visual naming and sentence comprehension, visual-spatial ability, and "general semantic knowledge about the world". They also noted an improved vocabulary and general knowledge base after 18 months. C.L.s episodic memory, on the other hand, was far below expectations: She could not retain daily events, where she had gone on vacation, the names of places she had been, and other such information. However, this study and others like it are susceptible to subjectivity, since it is not always possible to clearly distinguish between episodic and semantic memory. For this reason, the topic remains controversial and debated. Familiarity and the fractionation of memory The right hippocampus is clearly necessary for familiarity in spatial tasks, whereas the left hippocampus is necessary for familiarity-based recollection in verbal tasks. Some researchers claim the hippocampus is important for the retrieval of memories, whereas adjacent cortical regions can support familiarity-based memories. These memory decisions are made based on matching already-existing memories (before the onset of pathology) to the current situation. According to Gilboa et al., patients with localized hippocampal damage can score well on a test if it is based on familiarity.Poreh et al. describe a case study of patient A.D., whose damage to the fornix rendered the hippocampus useless, but spared adjacent cortical areas – a fairly rare injury. When the patient was given a test with something with which he had some familiarity, the patient was able to score well. In general, however, A.D. had severely impaired episodic memory, but had some ability to learn semantic knowledge. Other studies show animals with similar injuries can recognize objects with which they are familiar, but, when the objects are presented in an unexpected context, they do not score well on recognition tests. Islands of memory Patients with anterograde amnesia have trouble recalling new information and new autobiographical events, but the data are less consistent in regard to the latter. Medveds and Hirst recorded the presence of islands of memory – detailed accounts – that were described by such patients. The island memories were a combination of semantic and episodic memories. The researchers recorded patients giving long narratives with a fair amount of detail that resembled memories that the patients had prior to the trauma. The appearance of islands of memory could have something to do with the functioning of adjacent cortical areas and the neocortex. In addition, the researchers suspect that the amygdala played a role in the narratives. Notable cases The most famous case reported is that of patient Henry Molaison, known as H.M., in March 1953. Molaisons chief complaint was the persistence of severe seizures and therefore had a bilateral lobectomy (both of his medial temporal lobes were removed). As a result, Molaison had bilateral damage to both the hippocampal formation and the perirhinal cortex. Molaison had average intelligence and perceptual ability and a decent vocabulary. However, he could not learn new words or remember things that had happened more than a few minutes earlier. He could remember anything from his childhood. If the memory was created from before his lobectomy, he still had the ability to retrieve it and remember. However, he was able to learn some new skills. He was the first well-documented case of severe anterograde amnesia, and was studied until his death in 2008.A similar case involved Clive Wearing, an accomplished musicologist who contracted a cold sore virus that attacked his brain, causing herpes simplex encephalitis. As a result, Wearing developed both anterograde and retrograde amnesia, so he has little memory of what happened before the virus struck him in 1985, and cannot learn new declarative knowledge after the virus struck him either. As a result of anterograde amnesia, Wearing repeatedly "wakes up" every day usually in 30-second intervals. He has a history of repeatedly recording these moments of waking up in his journal (e.g., On Sept 2, 2013, I woke up, etc. etc.) and crossing out prior entries, as if the other moments of waking up were not real. His episodic memory is nonfunctional (so he does not consciously recall having woken up 30 seconds prior). Clive is often elated to see his wife, as if he has not seen her for a while. Despite this, however, Wearing maintained his ability to play the piano and conduct choirs. This case is significant because it demonstrates declarative and procedural memory are separate. Therefore, despite anterograde amnesia preventing Wearing from learning new bits of information that can be explained in words (declarative memory), and also preventing him from storing new memories of events or episodes (also part of declarative memory), he has little trouble in retaining his musical abilities (procedural memory), though he has no conscious memory of having learned music.Another case in the literature is Eugene Pauly, known as E.P., a severely amnesic patient (owing to viral encephalitis) who was able to learn three-word sentences. He performed better on consecutive tests over a 12-week period (24 study sessions). However, when asked how confident he was about the answers, his confidence did not appear to increase. Bayley and Squire proposed his learning was similar to the process required by procedural memory tasks; E.P. could not get the answers right when one word in the three-word sentence was changed or the order of words was changed, and his ability to answer correctly, thus, became more of a "habit". Bayley and Squire claim the learning may have happened in the neocortex, and it happened without the conscious knowledge of E.P. They hypothesized the information may be acquired directly by the neocortex (to which the hippocampus projects) when there is repetition. This case illustrates the difficulty in separating procedural from declarative tasks; this adds another dimension to the complexity of anterograde amnesia. In fiction Notable examples include Lucy Whitmore in 50 First Dates, Jonathan Archer in the Star Trek: Enterprise episode "Twilight", Joseph Gordon-Levitt in The Lookout, Kaori Fujimiya in One Week Friends, Chihiro Shindou in Ef: A Fairy Tale of the Two, Christine Lucas in Before I Go to Sleep, Gus in Remember Sunday. Christopher Nolans psychological crime film Memento (2000) contains a distinguished depiction of anterograde amnesia, in that the memory-impaired protagonist Leonard Shelby is trying to identify and kill the man who raped and murdered his wife, and does so through a system of writing crucial details related to the search on his body and on the blank spaces of Polaroid photographs. Mental health experts have described Memento as one of the most accurate depictions of amnesia in film history, an accuracy that was enhanced by the films fragmented, non-linear structure that mimics the protagonists memory problems.Dory, the happy-go-lucky Regal Blue Tang from Finding Nemo (2003) and Finding Dory (2016), suffers from anterograde amnesia. While Dory forgets conversations within minutes of having them, she never quite forgets who she is, or the fact that she has short-term memory loss, and can therefore explain her bizarre behavior to those around her.Ghajini (2008), a Hindi language film of India based on Memento, in which the main protagonist Sanjay Singhania played by Amir Khan has short-term memory loss, this variant of amnesia. In the film he is behind Ghajini, the killer of his fiancée Kalpana. In the TV series Perception, an episode revolved around a crime victim with this condition. The main character Latro in Gene Wolfes novels Soldier of the Mist, and the anime characters Vash the Stampede from Trigun and Index and Tōma from A Certain Magical Index had both retrograde and anterograde amnesia. The disorder has also been portrayed in music by English the Caretaker in Theoretically Pure Anterograde Amnesia (2005).In the 1965 film 36 Hours, Rod Taylor plays Nazi Major Walter Gerber, a psychiatrist who has developed an effective method for treating German soldiers with what is now known as PTSD – and for painlessly extracting information from Allied prisoners. The technique involves convincing patients that years have passed, the war is over, and that they have anterograde amnesia, which supposedly can be cured with talk therapy. A few days before D-Day, U.S. Army Major Jeff Pike (James Garner) is drugged, kidnapped and taken to what appears to be a hospital run by American Occupation Forces, where his appearance is altered overnight. Pike knows that the invasion is aimed at Normandy, not Pas de Calais, as the Nazi high command expects. He buys Gerbers explanation of anterograde amnesia – using the double doors of a wardrobe as illustration – and speaks casually of Normandy. Salt in a papercut alerts him to the horrible truth, and the drama proceeds from there. In the 2011 light novel Danganronpa Zero, the protagonist and "Ultimate Analyst" Ryoko Otonashi has anterograde amnesia as a result of "The Tragedy", keeping note of her memories by writing into a journal at all times and using her speedreading to keep herself up to date. Seen to be her boyfriend and "Ultimate Neurologist" Yasuke Matsuda, Ryoko witnesses a murder committed by Junko Enoshima, before being mistaken for wanted murderer and Tragedy perpetrator Izuru Kamukura by the "Ultimate Bodyguard" Madarai octuplets. After teaming up with perverted "Ultimate Secret Agent" Yuto Kamishiro in an attempt to discover the perpetrator behind the Tragedy, Ryoko learns that she herself was personally involved in the event as the true Junko, the Junko she met having been her non-identical twin sister Mukuro Ikusaba (with whom she shared Matsuda as a boyfriend) attempting to trigger her memories, which Matsuda had been suppressing on Junkos own request both to clear her of suspicion in the events off the Tragedy, attempt to cure her depression, and test wiping the memories of others. Attempting to subdue Ryoko, Matsuda accidentally restores her memories of being Junko and his fatally stabbed, before wishing Junko success in her planned actions with Izuru and Mukuro: collapsing world society and launching a "killing game". In the 2016 video game Phoenix Wright: Ace Attorney – Spirit of Justice, the character Sorin Sprocket is eventually revealed to have anterograde amnesia, which he developed after unintentionally causing a car accident which killed his sister. This causes his memories to completely reset every time he wakes up from sleeping, to the day after this accident. This depiction is notable for demonstrating the relationship issues that arise between Sorin and his fiancée, Ellen Wyatt, as a result of this disorder, most noticeably with how Sorins feelings towards her to coming across

Anterograde amnesia

as distant and cold. As the storyline continues, however, the player comes to uncover that Sorin in fact deeply loves his fiancée, and is able to maintain this love despite his disorder, but in fact feels a sense of guilt over the fact that he has to constantly remind himself of the fact that this love exists inside of him every day, due to his disorder. It is also noticeable in that it depicts how Sorin deals with his disorder, by keeping a journal where he writes down every detail of every day after his sisters death. He carries this journal around everywhere he goes as a substitution to his memories, and uses what is written in the notebook to become aware each time he wakes up of the fact that he has his condition, what the current date apparently is, and everything important that have apparently occurred on every day since he first developed the condition. The episode also deals with legal issues concerning the disorder, when it is debated during Ellen Wyatts trial as to whether Sorins journal can be considered a proper substitution to his memories for the sake of viable witness testimony. Dangers imposed by this also come into play when it is revealed that a page in Sorins journal had been altered by someone, which causes him to go into mental collapse that any of his other memories and thoughts could also have arisen from someone elses manipulation.In the episode "Pimemento" of Brooklyn Nine-Nine, Adrian Pimento develops an artificial form of anterograde amnesia after being drugged by his therapist, which is a main plot point of the episode. See also Transient global amnesia References Other sources == External links ==

Typhus

Typhus, also known as typhus fever, is a group of infectious diseases that include epidemic typhus, scrub typhus, and murine typhus. Common symptoms include fever, headache, and a rash. Typically these begin one to two weeks after exposure.The diseases are caused by specific types of bacterial infection. Epidemic typhus is due to Rickettsia prowazekii spread by body lice, scrub typhus is due to Orientia tsutsugamushi spread by chiggers, and murine typhus is due to Rickettsia typhi spread by fleas.Vaccines have been developed, but none are commercially available. Prevention is achieved by reducing exposure to the organisms that spread the disease. Treatment is with the antibiotic doxycycline. Epidemic typhus generally occurs in outbreaks when poor sanitary conditions and crowding are present. While once common, it is now rare. Scrub typhus occurs in Southeast Asia, Japan, and northern Australia. Murine typhus occurs in tropical and subtropical areas of the world.Typhus has been described since at least 1528. The name comes from the Greek tûphos (τῦφος) meaning fever or delusion, describing the state of mind of those infected. While "typhoid" means "typhus-like", typhus and typhoid fever are distinct diseases caused by different types of bacteria. Note, however, that in some languages such as German, typhus does mean "typhoid fever". Signs and symptoms These signs and symptoms refer to epidemic typhus, as it is the most important of the typhus group of diseases.Signs and symptoms begin with sudden onset of fever and other flu-like symptoms about one to two weeks after being infected. Five to nine days after the symptoms have started, a rash typically begins on the trunk and spreads to the extremities. This rash eventually spreads over most of the body, sparing the face, palms, and soles. Signs of meningoencephalitis begin with the rash and continue into the second or third weeks. Other signs of meningoencephalitis include sensitivity to light (photophobia), altered mental status (delirium), or coma. Untreated cases are often fatal. Causes Multiple diseases include the word "typhus" in their descriptions. Types include: Prevention As of 2020, no vaccine is commercially available. A vaccine has been in development for scrub typhus known as the scrub typhus vaccine. Treatment The American Public Health Association recommends treatment based upon clinical findings and before culturing confirms the diagnosis. Without treatment, death may occur in 10% to 60% of people with epidemic typhus, with people over age 60 having the highest risk of death. In the antibiotic era, death is uncommon if doxycycline is given. In one study of 60 people hospitalized with epidemic typhus, no one died when given doxycycline or chloramphenicol. Epidemiology According to the World Health Organization, the current death rate from typhus is about one of every 5,000,000 people per year.Only a few areas of epidemic typhus exist today. Since the late 20th century, cases have been reported in Burundi, Rwanda, Ethiopia, Algeria, and a few areas in South and Central America.Except for two cases, all instances of epidemic typhus in the United States have occurred east of the Mississippi River. An examination of a cluster of cases in Pennsylvania concluded the source of the infection was flying squirrels. Sylvatic cycle (diseases transmitted from wild animals) epidemic typhus remains uncommon in the US. The Centers for Disease Control and Prevention have documented only 47 cases from 1976 to 2010. An outbreak of flea-borne murine typhus was identified in downtown Los Angeles, California, in October 2018. History Middle Ages The first reliable description of typhus appears in 1489 AD during the Spanish siege of Baza against the Moors during the War of Granada (1482–1492). These accounts include descriptions of fever; red spots over arms, back, and chest; attention deficit, progressing to delirium; and gangrenous sores and the associated smell of rotting flesh. During the siege, the Spaniards lost 3,000 men to enemy action, but an additional 17,000 died of typhus.In historical times, "jail fever" or "gaol fever" was common in English prisons, and is believed by modern authorities to have been typhus. It often occurred when prisoners were crowded together into dark, filthy rooms where lice spread easily. Thus, "imprisonment until the next term of court" was often equivalent to a death sentence. Prisoners brought before the court sometimes infected members of the court. The Black Assize of Exeter 1586 was another notable outbreak. During the Lent assizes court held at Taunton in 1730, gaol fever caused the death of the Lord Chief Baron, as well as the High Sheriff, the sergeant, and hundreds of others. During a time when persons were executed for capital offenses, more prisoners died from gaol fever than were put to death by all the public executioners in the British realm. In 1759, an English authority estimated that each year, a quarter of the prisoners had died from gaol fever. In London, gaol fever frequently broke out among the ill-kept prisoners of Newgate Prison and then moved into the general city population. In May 1750, the Lord Mayor of London, Sir Samuel Pennant, and many court personnel were fatally infected in the courtroom of the Old Bailey, which adjoined Newgate Prison. Early modern epidemics Epidemics occurred routinely throughout Europe from the 16th to the 19th centuries, including during the English Civil War, the Thirty Years War, and the Napoleonic Wars. Pestilence of several kinds raged among combatants and civilians in Germany and surrounding lands from 1618 to 1648. According to Joseph Patrick Byrne, "By wars end, typhus may have killed more than 10 percent of the total German population, and disease in general accounted for 90 percent of Europes casualties." 19th century During Napoleons retreat from Moscow in 1812, more French soldiers died of typhus than were killed by the Russians.A major epidemic occurred in Ireland between 1816 and 1819, during the famine caused by a worldwide reduction in temperature known as the Year Without a Summer. An estimated 100,000 people perished. Typhus appeared again in the late 1830s, and yet another major typhus epidemic occurred during the Great Irish Famine between 1846 and 1849. The Irish typhus spread to England, where it was sometimes called "Irish fever" and was noted for its virulence. It killed people of all social classes, as lice were endemic and inescapable, but it hit particularly hard in the lower or "unwashed" social strata.In the United States, a typhus epidemic broke out in Philadelphia in 1837 and killed the son of Franklin Pierce (14th President of the United States) in Concord, New Hampshire, in 1843. Several epidemics occurred in Baltimore, Memphis, and Washington, DC, between 1865 and 1873. Typhus was also a significant killer during the US Civil War, although typhoid fever was the more prevalent cause of US Civil War "camp fever". Typhoid fever is caused by the bacterium Salmonella enterica Serovar Typhi.In Canada alone, the typhus epidemic of 1847 killed more than 20,000 people from 1847 to 1848, mainly Irish immigrants in fever sheds and other forms of quarantine, who had contracted the disease aboard the crowded coffin ships in fleeing the Great Irish Famine. Officials neither knew how to provide sufficient sanitation under conditions of the time nor understood how the disease spread. 20th century Typhus was endemic in Poland and several neighboring countries prior to World War I (1914–1918), but became epidemic during the war. Delousing stations were established for troops on the Western Front during World War I, but typhus ravaged the armies of the Eastern Front, where over 150,000 died in Serbia alone. Fatalities were generally between 10% and 40% of those infected and the disease was a major cause of death for those nursing the sick.In 1922, the typhus epidemic reached its peak in Soviet territory, with some 20 to 30 million cases in Russia. Although typhus had ravaged Poland with some 4 million cases reported, efforts to stem the spread of disease in that country had largely succeeded by 1921 through the efforts of public health pioneers such as Hélène Sparrow and Rudolf Weigl. In Russia during the civil war between the White and Red Armies, epidemic typhus killed 2–3 million people, many of whom were civilians. In 1937 and 1938 there was a typhus epidemic in Chile.During World War II, many German POWs after the loss at Stalingrad died of typhus. Typhus epidemics killed those confined to POW camps, ghettos, and Nazi concentration camps who were held in unhygienic conditions. Pictures of mass graves including people who died from typhus can be seen in footage shot at Bergen-Belsen concentration camp. Among thousands of prisoners in concentration camps such as Theresienstadt and Bergen-Belsen who died of typhus were Anne Frank, age 15, and her sister Margot, age 19 in the latter camp. The first typhus vaccine was developed by the Polish zoologist Rudolf Weigl in the interwar period; the vaccine did not prevent the disease but reduced its mortality. 21st century Beginning in 2018, a typhus outbreak spread through Los Angeles County primarily affecting homeless people. In 2019, city attorney Elizabeth Greenwood revealed that she, too, was infected with typhus as a result of a flea bite at her office in Los Angeles City Hall. Pasadena also experienced a sudden uptick in typhus with 22 cases in 2018 but, without being able to attribute this to one location, the Pasadena Public Health Department did not identify the cases as an "outbreak". == References ==

Arteritis

Arteritis is the inflammation of the walls of arteries, usually as a result of infection or autoimmune response. Arteritis, a complex disorder, is still not entirely understood. Arteritis may be distinguished by its different types, based on the organ systems affected by the disease. A complication of arteritis is thrombosis, which can be fatal. Arteritis and phlebitis are forms of vasculitis. Signs and Symptoms Symptoms of general arteritis may include: Inflammation Fever Increased production of red blood cells (erythrocytes) Limping Reduced pulse Diagnosis Diagnosis of arteritis is based on unusual medical symptoms. Similar symptoms may be caused by a number of other conditions, such as Ehlers-Danlos syndrome and Marfan syndrome (both heritable disorders of connective tissue), tuberculosis, syphilis, spondyloarthropathies, Cogans syndrome, Buergers, Behcets, and Kawasaki disease. Various imaging techniques may be used to diagnose and monitor disease progression. Imaging modalities may include direct angiography, magnetic resonance angiography, and ultrasonography.Angiography is commonly used in the diagnosis of Takayasu arteritis, especially in the advanced stages of the disease, when arterial stenosis, occlusion, and aneurysms may be observed. However, angiography is a relatively invasive investigation, exposing patients to large doses of radiation, so is not recommended for routine, long-term monitoring of disease progression in patients with Takayasu arteritis.Computed tomography angiography can determine the size of the aorta and its surrounding branches, and can identify vessel wall lesions in middle to late stages of arteritis. CTA can also show the blood flow within the blood vessels. Like angiography, CTA exposes patients to high dosages of radiation.Magnetic resonance angiography is used to diagnose Takayasu arteritis in the early stages, showing changes such as the thickening of the vessel wall. Even small changes may be measured, making MRA a useful tool for monitoring disease progression without exposing patients to the radiation of direct angiography or CTA. MRA is an expensive investigation, and shows calcification of the aorta and distal branches less clearly than other imaging methods.Ultrasonography is an ideal method of diagnosing patients in early stages of arteritis when inflammation in the vessel walls occurs. It can also show the blood flow within the blood vessels. Ultrasonography is a popular first-line investigation for diagnosis because it is relatively quick, cheap, noninvasive, and does not expose patients to radiation. It is also used for long-term monitoring of disease progression in Takayasu arteritis. Not all vascular lesions are visible on ultrasound, and the accuracy of the scan depends, to some extent, on the person reading the scan, as the results are observed in real time. Types Arteritis may be primary or secondary to some other disease process. The primary types are: An example of a secondary arteritis is arteritis caused by infection with the fungal pathogen Candida albicans. Giant cell arteritis Giant cell arteritis contains two different types of arteritides that are almost indistinguishable from one another. It includes two types, temporal arteritis and Takayasu arteritis. Both types contain an occupancy of medium- and larger-sized arteries which are categorized based on the infiltration of the giant cells. Takayasu arteritis This type of arteritis is most common in females, with a median age of 25 years. Takayasu arteritis is more common in women of Asian descent who are in their reproductive years. However, over the past decades, its incidence in Africa, Europe, and North America has been increasing. Takayasu arteritis is an inflammatory disease that mainly affects the larger vessels such as the aorta and its surrounding branches. Research focused on Takayasu arteritis in the western parts of the world remains limited. An estimation suggests that, each year, the number of cases per million people is 2.6. Temporal arteritis Temporal arteritis, the second type of giant cell arteritis, is also a chronic, inflammatory disease involving mid- to large-sized arteries. Temporal arteritis has a higher incidence in people of Scandinavian descent. However, the incidence rate differs based on population, region and races. Temporal arteritis is not uncommon in North America. The incidence rate is around 0.017% for individuals over 50 years of age.Symptoms of temporal arteritis are classified as specific and nonspecific.Nonspecific symptoms: Headache Low grade fever Sweating Anorexia (loss of appetite) Weight loss General malaiseSpecific symptoms: Claudication of the jaw Engorged, tender vesselsSpecific symptoms usually develop in the advanced stages of temporal arteritis.Polyarteritis nodosa of unknown mechanism can cause testicular pain. It is often associated with aneurysms and Hepatitis B. Treatment Medications The first-line treatment for arteritis is oral glucocorticoid (steroid) medication, such as prednisone, taken daily for a period of three months. After this initial phase, the medication may be reduced in dose or frequency, e.g. every other day, if possible. If the disease worsens with the new treatment schedule, a cytotoxic medication may be given, in addition to the glucocorticoid. Commonly used cytotoxic agents include azathioprine, methotrexate, or cyclophosphamide. The dose of glucocorticoid medication may be decreased if response to treatment is good. This medication may be reduced gradually once the disease becomes inactive, slowly tapering the dose (to allow the body time to adjust) until the medication may be stopped completely. Conversely, if the disease remains active, the medication will need to be increased. After six months, if the medication cannot be reduced in frequency to alternate days, or if in 12 months the medications cannot be stopped completely, then treatment is deemed to have failed.Pulsed therapy is an alternative method of administering the medications above, using much higher doses over a short period of time (a pulse), to reduce the inflammation within the arteries. Methylprednisolone, a glucocorticoid, is often used for pulse therapy; cyclophosphamide is an alternative. This method has been shown to be successful for some patients. Immunosuppressive pulse therapy, such as with cyclophosphamide, has also demonstrated relief of symptoms associated with arteritis. References == External links ==

Ancylostomiasis

Ancylostomiasis is a hookworm disease caused by infection with Ancylostoma hookworms. The name is derived from Greek ancylos αγκύλος "crooked, bent" and stoma στόμα "mouth". Ancylostomiasis is also known as miners anaemia, tunnel disease, brickmakers anaemia and Egyptian chlorosis. Helminthiasis may also refer to ancylostomiasis, but this term also refers to all other parasitic worm diseases as well. In the United Kingdom, if acquired in the context of working in a mine, the condition is eligible for Industrial Injuries Disability Benefit. It is a prescribed disease (B4) under the relevant legislation.§Ancylostomiasis is caused when hookworms, present in large numbers, produce an iron deficiency anemia by sucking blood from the hosts intestinal walls. Signs and symptoms Depending on the organism, the signs and symptoms vary. Ancylostoma duodenale and Necator americanus can enter the blood stream while Ancylostoma braziliensis cannot. Signs and symptoms of Ancylostoma duodenale and Necator americanus are given in corresponding page.In Ancylostoma braziliensis as the larvae are in an abnormal host, they do not mature to adults but instead migrate through the skin until killed by the hosts inflammatory response. This migration causes local intense itching and a red serpiginous lesion. Treatment with a single dose of oral ivermectin results in cure rates of 94–100%. Causes The infection is usually contracted by people walking barefoot over contaminated soil. In penetrating the skin, the larvae may cause an allergic reaction. It is due to the itchy patch at the site of entry that the early infection gets its nickname "ground itch". Once larvae have broken through the skin, they enter the bloodstream and are carried to the lungs (however, unlike ascarids, hookworms do not usually cause pneumonia). The larvae migrate from the lungs up the windpipe to be swallowed and carried back down to the intestine. If humans come into contact with larvae of the dog hookworm or the cat hookworm, or of certain other hookworms that do not infect humans, the larvae may penetrate the skin. Sometimes, the larvae are unable to complete their migratory cycle in humans. Instead, the larvae migrate just below the skin producing snake-like markings. This is referred to as a creeping eruption or cutaneous larva migrans. Diagnosis They commonly infect the skin, eyes, and viscera in humans. Ancylostoma brasiliensis causes cutaneous larva migrans. Toxocara causes visceral larva migrans. Prevention Control of this parasite should be directed against reducing the level of environmental contamination. Treatment of heavily infected individuals is one way to reduce the source of contamination (one study has estimated that 60% of the total worm burden resides in less than 10% of the population). Other obvious methods are to improve access to sanitation, e.g. toilets, but also convincing people to maintaining them in a clean, functional state, thereby making them conducive to use. Treatment The drug of choice for the treatment of hookworm disease is mebendazole which is effective against both species, and in addition, will remove the intestinal worm Ascaris also, if present. The drug is very efficient, requiring only a single dose and is inexpensive. However, treatment requires more than giving the anthelmintic, the patient should also receive dietary supplements to improve their general level of health, in particular iron supplementation is very important. Iron is an important constituent of a multitude of enzyme systems involved in energy metabolism, DNA synthesis and drug detoxification.An infection of N. americanus parasites can be treated by using benzimidazoles, albendazole, and mebendazole. A blood transfusion may be necessary in severe cases of anemia. Light infections are usually left untreated in areas where reinfection is common. Iron supplements and a diet high in protein will speed the recovery process. In a case study involving 56–60 men with Trichuris trichiura and/or N. americanus infections, both albendazole and mebendazole were 90% effective in curing T. trichiura. However, albendazole had a 95% cure rate for N. americanus, while mebendazole only had a 21% cure rate. This suggests albendazole is most effective for treating both T. trichiura and N. americanus.During the 1910s, common treatments for hookworm included thymol, 2-naphthol, chloroform, gasoline, and eucalyptus oil. By the 1940s, the treatment of choice was tetrachloroethylene, given as 3 to 4 cc in the fasting state, followed by 30 to 45 g of sodium sulfate. Tetrachloroethylene was reported to have a cure rate of 80 percent for Necator infections, but 25 percent in Ancylostoma infections, requiring re-treatment. Epidemiology Hookworm anaemia was first described by Wilhelm Griesenger in Egypt, Cairo in 1852. He found thousands of adult ancylostomes in the small bowel of a 20-year old soldier who was suffering from severe diarrhoea and anaemia (labelled at the time as Egyptian chlorosis). The subject was revisited in Europe when there was an outbreak of "miners anaemia" in Italy. During the construction of the Gotthard Tunnel in Switzerland (1871–81), a large number of miners suffered from severe anaemia of unknown cause. Medical investigations let to the understanding that it was caused by Ancylostoma duodenale (favoured by high temperatures and humidity) and to "major advances in parasitology, by way of research into the aetiology, epidemiology and treatment of ancylostomiasis".Hookworms still account for high proportion of debilitating disease in the tropics and 50–60,000 deaths per year can be attributed to this disease. References == External links ==

Spasm

A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a muscle cramp which is accompanied by a sudden burst of pain. A muscle cramp is usually harmless and ceases after a few minutes. It is typically caused by ion imbalance or muscle overload. There are other causes of involuntary muscle contractions, and some of these may cause a health problem. Description and causes Various kinds of involuntary muscle activity may be referred to as a "spasm". A spasm may be a muscle contraction caused by abnormal nerve stimulation or by abnormal activity of the muscle itself. A spasm may lead to muscle strains or tears in tendons and ligaments if the force of the spasm exceeds the tensile strength of the underlying connective tissue. This can occur with a particularly strong spasm or with weakened connective tissue. A hypertonic muscle spasm is a condition of chronic, excessive muscle tone (i.e., tension in a resting muscle). This is the amount of contraction that remains when a muscle is not working. A true hypertonic spasm is caused by malfunctioning feedback nerves. This is much more serious and is permanent unless treated. In this case, the hypertonic muscle tone is excessive, and the muscles are unable to relax. A subtype of spasm is colic. This is an episodic pain caused by spasm of smooth muscle in a particular organ (e.g., the bile duct). A characteristic of colic is the sensation of having to move about, and the pain may induce nausea or vomiting. See also References External links NIH Medical Encyclopedia How Stuff Works "Spasm" . New International Encyclopedia. 1905.

Gerstmann–Sträussler–Scheinker syndrome

Gerstmann–Sträussler–Scheinker syndrome (GSS) is an extremely rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age. It is exclusively heritable, and is found in only a few families all over the world. It is, however, classified with the transmissible spongiform encephalopathies (TSE) due to the causative role played by PRNP, the human prion protein. GSS was first reported by the Austrian physicians Josef Gerstmann, Ernst Sträussler and Ilya Scheinker in 1936.Familial cases are associated with autosomal-dominant inheritance.Certain symptoms are common to GSS, such as progressive ataxia, pyramidal signs, and dementia; they worsen as the disease progresses. Symptoms and signs Symptoms start with slowly developing dysarthria (difficulty speaking) and cerebellar truncal ataxia (unsteadiness) and then the progressive dementia becomes more evident. Loss of memory can be the first symptom of GSS. Extrapyramidal and pyramidal symptoms and signs may occur and the disease may mimic spinocerebellar ataxias in the beginning stages. Myoclonus (spasmodic muscle contraction) is less frequently seen than in Creutzfeldt–Jakob disease. Many patients also exhibit nystagmus (involuntary movement of the eyes), visual disturbances, and even blindness or deafness. The neuropathological findings of GSS include widespread deposition of amyloid plaques composed of abnormally folded prion protein.Four clinical phenotypes are recognized: typical GSS, GSS with areflexia and paresthesia, pure dementia GSS and Creutzfeldt-Jakob disease-like GSS. Causes GSS is part of a group of diseases called transmissible spongiform encephalopathies. These diseases are caused by prions, which are a class of pathogenic proteins that are resistant to proteases. These prions then form clusters in the brain, which are responsible for the neurodegenerative effects seen in patients.The P102L mutation, which causes a substitution of proline to a leucine in codon 102, has been found in the prion protein gene (PRNP, on chromosome 20) of most affected individuals. Therefore, it appears this genetic change is usually required for the development of the disease. Diagnosis GSS can be identified through genetic testing. Testing for GSS involves a blood and DNA examination in order to attempt to detect the mutated gene at certain codons. If the genetic mutation is present, the patient will eventually develop GSS. Treatment There is no cure for GSS, nor is there any known treatment to slow the progression of the disease. Therapies and medication are aimed at treating or slowing down the effects of the symptoms. The goal of these treatments is to try to improve the patients quality of life as much as possible. There is some ongoing research to find a cure, with one of the most prominent examples being the PRN100 monoclonal antibody. Prognosis GSS is a disease that progresses slowly, lasting roughly 2–10 years, with an average of approximately five years. The disease ultimately results in death, most commonly from the patient either going into a coma, or from a secondary infection due to the patients loss of bodily functions. Research Prion diseases, also called transmissible spongiform encephalopathies (TSEs), are neurodegenerative diseases of the brain thought to be caused by a protein that converts to an abnormal form called a prion. GSS is a very rare TSE, making its genetic origin nearly impossible to determine. It is also challenging to find any patients with GSS, as the disease tends to be underreported, due to its clinical similarity to other diseases, and has been found in only a few countries. In 1989, the first mutation of the prion protein gene was identified in a GSS family. The largest of these families affected by GSS is the Indiana Kindred, spanning over 8 generations, and includes over 3,000 people, with 57 individuals known to be affected. GSS was later realized to have many different gene mutation types, varying in symptom severity, timing and progression. Doctors in different parts of the world are in the process of uncovering more generations and families who have the mutation. Notes External links Gerstmann–Sträussler–Scheinker syndrome, MedicineNet.com

Fear of flying

Fear of flying is a fear of being on an airplane, or other flying vehicle, such as a helicopter, while in flight. It is also referred to as flying anxiety, flying phobia, flight phobia, aviophobia, aerophobia, or pteromechanophobia (although aerophobia also means a fear of drafts or of fresh air).Acute anxiety caused by flying can be treated with anti-anxiety medication. The condition can be treated with exposure therapy, which works better when combined with cognitive behavioral therapy. Signs and symptoms People with fear of flying experience intense, persistent fear or anxiety when they consider flying, as well as during flying. They will avoid flying if they can, and the fear, anxiety, and avoidance cause significant distress and impair their ability to function. Take-off, bad weather, and turbulence appear to be the most anxiety provoking aspects of flying.The most extreme manifestations can include panic attacks or vomiting at the mere sight or mention of an aircraft or air travel.Around 60% of people with fear of flying report having some other anxiety disorder. Cause The causes of flight phobia and the mechanisms by which it is maintained were not well understood as of 2016. It is not clear if it is really one condition; it appears to be heterogenous. It appears that some people get aerophobia from being or having claustrophobia to the small spaces inside the fuselage of the plane or helicopter. Diagnosis The diagnosis is clinical. It is often difficult to determine if the specific phobia of fear of flight should be the primary diagnosis, or if fear of flying is a symptom of a generalized anxiety disorder or another anxiety disorder such as agoraphobia or claustrophobia. Classification Fear of flying is a specific phobia classified as such in the DSM-5. Management Acute anxiety caused by flying can be treated with anti-anxiety medication. The condition can be treated with exposure therapy, including use of virtual reality equipment, which works better when combined with cognitive behavioral therapy. Relaxation techniques and education about aviation safety can also be helpful in combination with other approaches.A new and advanced treatment for aviophobia is virtual reality exposure therapy. This type of treatment uses computer technology where the patient enters a virtual reality of flying. Virtual reality exposure therapy Effective treatment for phobias such as fear of flying would be one that activates and modifies the fear structure. Activation of the fear structure can be achieved by exposing the patient to the feared stimuli, flying in this case, to elicit the fearful response. Modification of the fear structure can be achieved by the processes of habituation and extinction after eliciting the fearful response several times. A new and advanced treatment for aviophobia is virtual reality exposure therapy (VRET). This type of treatment uses computer technology where the patient virtually experiences flying. This experience includes visual, auditory, and motion stimuli to imitate flying in a plane as close as possible. Thus, VRET is considered an effective treatment for aviophobia. While it can be argued that vivo exposure treatment, patients being exposed to an aircraft, is the most effective way of treatment, but VRET is more cost-effective, accessible, less time-consuming, and requires less organization. Another advantage of VRET over vivo exposure treatment is that it focuses on the main reason that elicits fear of flying easily. For example, if the patients most anxiety-inducing-component is takeoff, in VRET the patient would be exposed to a plane takeoff repeatedly while in vivo exposure the patient would have to wait for the plane to land and then take off again. Outcomes Studies of interventions like CBT have reported rates of reduction in anxiety of around 80%; however, there is little evidence that any treatment can eliminate fear of flying. Epidemiology Estimates for prevalence have ranged between 2.5% and 40%; estimates on the lower end are probably generated through studies where the condition is diagnosed by a professional, and the higher end probably includes people who have diagnosed themselves. History Fear of flying was first discussed in the biomedical literature by a doctor in the UK at the end of World War I, who called it "aero-neurosis" and was describing pilots and crew who were or became anxious about flying. It was not much discussed until the 1950s and rise of commercial air travel and the vogue in psychoanalysis. Starting in the 1970s fear of flying was addressed through behavioral and cognitive approaches. Society and culture Immediately after the September 11 attacks, Americans chose to travel more by car instead of flying; because of the extra traffic, around 350 more people died in traffic accidents than would have normally occurred.A number of celebrities have suffered from a fear of flying, including former Arsenal FC and Netherlands footballer Dennis Bergkamp, famously dubbed the "non-flying Dutchman", Agnetha Fältskog, and rockstar David Bowie. Research directions As of 2016, the causes of fear of flying as well as the psychological mechanisms through which it were persists had not been well researched. A few studies had looked at whether mechanisms like illusory correlation and expectancy bias were present in all or most people with fear of flying as well as other specific phobias; these studies have not led to clear outcomes.Research into the most effective ways to treat or manage fear of flying is difficult (as it is with other counselling or behavioral interventions) due to the inability to include a placebo or other control arm in such studies. See also List of phobias Health hazards of air travel Flight shame == References ==

Less

Less or LESS may refer to: fewer than,: not as much. Computing less (Unix), a Unix utility program Less (stylesheet language), a dynamic stylesheet language Large-Scale Scrum (LeSS), a product development framework that extends Scrum Other uses -less, a privative suffix in English Lunar Escape Systems, a series of proposed emergency spacecraft for the Apollo Program Christian Friedrich Lessing (1809–1862), (author abbreviation Less.) for German botanist Less (novel), a 2017 novel by Andrew Sean Greer See also Fewer versus less Less is more (disambiguation) All pages with titles beginning with Less All pages with titles containing Less

System

A system is a group of interacting or interrelated elements that act according to a set of rules to form a unified whole. A system, surrounded and influenced by its environment, is described by its boundaries, structure and purpose and expressed in its functioning. Systems are the subjects of study of systems theory and other systems sciences. Systems have several common properties and characteristics, including structure, function(s), behavior and interconnectivity. Etymology The term system comes from the Latin word systēma, in turn from Greek σύστημα systēma: "whole concept made of several parts or members, system", literary "composition". History According to Marshall McLuhan, "System" means "something to look at". You must have a very high visual gradient to have systematization. But in philosophy, prior to Descartes, there was no "system". Plato had no "system". Aristotle had no "system". In the 19th century the French physicist Nicolas Léonard Sadi Carnot, who studied thermodynamics, pioneered the development of the concept of a system in the natural sciences. In 1824 he studied the system which he called the working substance (typically a body of water vapor) in steam engines, in regards to the systems ability to do work when heat is applied to it. The working substance could be put in contact with either a boiler, a cold reservoir (a stream of cold water), or a piston (on which the working body could do work by pushing on it). In 1850, the German physicist Rudolf Clausius generalized this picture to include the concept of the surroundings and began to use the term working body when referring to the system. The biologist Ludwig von Bertalanffy became one of the pioneers of the general systems theory. In 1945 he introduced models, principles, and laws that apply to generalized systems or their subclasses, irrespective of their particular kind, the nature of their component elements, and the relation or forces between them.Norbert Wiener and Ross Ashby, who pioneered the use of mathematics to study systems, carried out significant development in the concept of a system.In the 1980s John Henry Holland, Murray Gell-Mann and others coined the term complex adaptive system at the interdisciplinary Santa Fe Institute. Concepts Environment and boundaries Systems theory views the world as a complex system of interconnected parts. One scopes a system by defining its boundary; this means choosing which entities are inside the system and which are outside—part of the environment. One can make simplified representations (models) of the system in order to understand it and to predict or impact its future behavior. These models may define the structure and behavior of the system.Natural and human-made systems There are natural and human-made (designed) systems. Natural systems may not have an apparent objective but their behavior can be interpreted as purposeful by an observer. Human-made systems are made with various purposes that are achieved by some action performed by or with the system. The parts of a system must be related; they must be "designed to work as a coherent entity" — otherwise they would be two or more distinct systems. Theoretical framework Most systems are open systems, exchanging matter and energy with their respective surroundings; like a car, a coffeemaker, or Earth. A closed system exchanges energy, but not matter, with its environment; like a computer or the project Biosphere 2. An isolated system exchanges neither matter nor energy with its environment. A theoretical example of such system is the Universe.Process and transformation process An open system can also be viewed as a bounded transformation process, that is, a black box that is a process or collection of processes that transform inputs into outputs. Inputs are consumed; outputs are produced. The concept of input and output here is very broad. For example, an output of a passenger ship is the movement of people from departure to destination.System model A system comprises multiple views. Man-made systems may have such views as concept, analysis, design, implementation, deployment, structure, behavior, input data, and output data views. A system model is required to describe and represent all these views.Systems architecture A systems architecture, using one single integrated model for the description of multiple views, is a kind of system model. Subsystem A subsystem is a set of elements, which is a system itself, and a component of a larger system. The IBM Mainframe Job Entry Subsystem family (JES1, JES2, JES3, and their HASP/ASP predecessors) are examples. The main elements they have in common are the components that handle input, scheduling, spooling and output; they also have the ability to interact with local and remote operators. A subsystem description is a system object that contains information defining the characteristics of an operating environment controlled by the system. The Data tests are performed to verify the correctness of the individual subsystem configuration data (e.g. MA Length, Static Speed Profile, …) and they are related to a single subsystem in order to test its Specific Application (SA). Analysis There are many kinds of systems that can be analyzed both quantitatively and qualitatively. For example, in an analysis of urban systems dynamics, A .W. Steiss defined five intersecting systems, including the physical subsystem and behavioral system. For sociological models influenced by systems theory, Kenneth D. Bailey defined systems in terms of conceptual, concrete, and abstract systems, either isolated, closed, or open. Walter F. Buckley defined systems in sociology in terms of mechanical, organic, and process models. Bela H. Banathy cautioned that for any inquiry into a system understanding its kind is crucial, and defined "natural" and "designed", i. e. artificial, systems. It is important not to confuse these abstract definitions. For example, natural systems include subatomic systems, living systems, the Solar System, galaxies, and the Universe, while artificial systems include man-made physical structures, hybrids of natural and artificial systems, and conceptual knowledge. The human elements of organization and functions are emphasized with their relevant abstract systems and representations. Artificial systems inherently have a major defect: they must be premised on one or more fundamental assumptions upon which additional knowledge is built. This is in strict alignment to the Gödels incompleteness theorems. The Artificial system can be defined as a "consistent formalized system which contains elementary arithmetic". These fundamental assumptions are not inherently deleterious, but they must by definition be assumed as true, and if they are actually false then the system is not as structurally integral as is assumed (i.e. it is evident that if the initial expession is false, then the Artificial system is not a "consistent formalized system"). For example, in geometry this is very evident in the postulation of theorems and extrapolation of proofs from them. George J. Klir maintained that no "classification is complete and perfect for all purposes", and defined systems as abstract, real, and conceptual physical systems, bounded and unbounded systems, discrete to continuous, pulse to hybrid systems, etc. The interactions between systems and their environments are categorized as relatively closed and open systems. It seems most unlikely that an absolutely closed system can exist or, if it did, that it could be known by man. Important distinctions have also been made between hard systems – technical in nature and amenable to methods such as systems engineering, operations research, and quantitative systems analysis – and soft systems that involve people and organisations, commonly associated with concepts developed by Peter Checkland and Brian Wilson through Soft Systems Methodology (SSM) involving methods such as action research and emphasis of participatory designs. Where hard systems might be identified as more "scientific", the distinction between them is often elusive. Cultural system A cultural system may be defined as the interaction of different elements of culture. While a cultural system is quite different from a social system, sometimes both together are referred to as a "sociocultural system". A major concern of the social sciences is the problem of order. Economic system An economic system is a mechanism (social institution) which deals with the production, distribution and consumption of goods and services in a particular society. The economic system is composed of people, institutions and their relationships to resources, such as the convention of property. It addresses the problems of economics, like the allocation and scarcity of resources. The international sphere of interacting states is described and analysed in systems terms by several international relations scholars, most notably in the neorealist school. This systems mode of international analysis has however been challenged by other schools of international relations thought, most notably the constructivist school, which argues that an over-large focus on systems and structures can obscure the role of individual agency in social interactions. Systems-based models of international relations also underlies the vision of the international sphere held by the liberal institutionalist school of thought, which places more emphasis on systems generated by rules and interaction governance, particularly economic governance. Applications Systems modeling is generally a basic principle in engineering and in social sciences. The system is the representation of the entities under concern. Hence inclusion to or exclusion from system context is dependent on the intention of the modeler. No model of a system will include all features of the real system of concern, and no model of a system must include all entities belonging to a real system of concern. Information and computer science In computer science and information science, system is a hardware system, software system, or combination, which has components as its structure and observable inter-process communications as its behavior. Again, an example will illustrate: There are systems of counting, as with Roman numerals, and various systems for filing papers, or catalogues, and various library systems, of which the Dewey Decimal Classification is an example. This still fits with the definition of components which are connected together (in this case to facilitate the flow of information). System can also refer to a framework, aka platform, be it software or hardware, designed to allow software programs to run. A flaw in a component or system can cause the component itself or an entire system to fail to perform its required function, e.g., an incorrect statement or data definition Engineering and physics In engineering and physics, a physical system is the portion of the universe that is being studied (of which a thermodynamic system is one major example). Engineering also has the concept of a system referring to all of the parts and interactions between parts of a complex project. Systems engineering is the branch of engineering that studies how this type of system should be planned, designed, implemented, built, and maintained. Expected result is the behavior predicted by the specification, or another source, of the component or system under specified conditions. Sociology, cognitive science and management research Social and cognitive sciences recognize systems in human person models and in human societies. They include human brain functions and mental processes as well as normative ethics systems and social/cultural behavioral patterns. In management science, operations research and organizational development (OD), human organizations are viewed as systems (conceptual systems) of interacting components such as subsystems or system aggregates, which are carriers of numerous complex business processes (organizational behaviors) and organizational structures. Organizational development theorist Peter Senge developed the notion of organizations as systems in his book The Fifth Discipline. Organizational theorists such as Margaret Wheatley have also described the workings of organizational systems in new metaphoric contexts, such as quantum physics, chaos theory, and the self-organization of systems. Pure logic There is also such a thing as a logical system. The most obvious example is the calculus developed simultaneously by Leibniz and Isaac Newton. Another example is George Booles Boolean operators. Other examples have related specifically to philosophy, biology, or cognitive science. Maslows hierarchy of needs applies psychology to biology by using pure logic. Numerous psychologists, including Carl Jung and Sigmund Freud have developed systems which logically organize psychological domains, such as personalities, motivations, or intellect and desire. Often these domains consist of general categories following a corollary such as a theorem. Logic has been applied to categories such as taxonomy, ontology, assessment, and hierarchies. Strategic thinking In 1988, military strategist, John A. Warden III introduced the Five Ring System model in his book, The Air Campaign, contending that any complex system could be broken down into five concentric rings. Each ring—Leadership, Processes, Infrastructure, Population and Action Units—could be used to isolate key elements of any system that needed change. The model was used effectively by Air Force planners in the First Gulf War. In the late 1990s, Warden applied his model to business strategy. See also References Bibliography External links Definitions of Systems and Models by Michael Pidwirny, 1999–2007. Publications with the title "System" (1600–2008) by Roland Müller. Definitionen von "System" (1572–2002) by Roland Müller, (most in German).

Hyperandrogenism

Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.Polycystic ovary syndrome accounts for about 70% of hyperandrogenism cases. Other causes include adrenal hyperplasia, hirsutism, insulin resistance, hyperprolactinemia, Cushings disease, certain types of cancers, and certain medications. Diagnosis often involves blood tests for testosterone, 17-hydroxyprogesterone, and prolactin, as well as a pelvic ultrasound.Treatment depends on the underlying cause. Symptoms of hyperandrogenism can be treated with birth control pills or antiandrogens, such as cyproterone acetate or spironolactone. Other palliative measures may include hair removal techniques.The earliest known description of the condition is attributed to Hippocrates.In 2011, the International Association of Athletics Federations (now World Athletics) and IOC (International Olympic Committee) released statements restricting the eligibility of female athletes with high testosterone, whether through hyperandrogenism or as a result of a difference in sex development (DSD). These regulations were referred to by both bodies as hyperandrogenism regulations and have led to athletes with DSDs being described as having hyperandrogenism. They were revised in 2019 to focus more specifically on DSDs. Signs and symptoms Hyperandrogenism affects 5–10% of women of reproductive age. Hyperandrogenism can affect both men and women but is more noticeable in women since elevated levels of androgens in women may facilitate virilization. Because hyperandrogenism is characterized by elevated male sex hormone levels, symptoms of hyperandrogenism in men are often negligible. Hyperandrogenism in women is typically diagnosed in late adolescence with a medical evaluation. The medical evaluation usually consists of a pelvic exam, observation of external symptoms, and a blood test measuring androgen levels. Symptoms may include the following: Women Hyperandrogenism, especially high levels of testosterone, can cause serious adverse effects if left untreated. High testosterone levels are associated with other health conditions such as obesity, hypertension, amenorrhea (cessation of menstrual cycles), and ovulatory dysfunction, which can lead to infertility. Prominent signs of hyperandrogenism are hirsutism (unwanted growth of hair, especially in the abdominal region and on the back), adult acne, deepening of the voice, and alopecia (balding).Hyperandrogenism has also been observed to increase insulin tolerance, which can lead to type two diabetes and dyslipidemia, such as high cholesterol. These effects may have psychological impacts, sometimes leading to social anxiety and depression, especially in adolescent girls and young women. Paired with obesity and hirsutism, it can cause the individual to have low self-esteem. Men Administration of high-dose testosterone in men over a course of weeks can cause an increase in aggression and hypomanic symptoms, though these were see in only a minority of subjects. Acute high-dose anabolic-androgenic steroid administration in males attenuates endogenous sex hormone production and affects the thyroid hormone axis. Effects on mood and aggression observed during high-dose anabolic-androgenic steroid administration may occur secondarily to hormonal changes. Many of the same signs and symptoms that are seen in women, such as alopecia and acne, may also be found in men. Enlargement of the prostate may also occur. Causes While hyperandrogenism in women can be caused by external factors, it can also appear spontaneously. Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by an excess of androgens produced by the ovaries. It is estimated that approximately 90% of women with PCOS demonstrate hypersecretion of these hormones. The cause of this condition is unknown. Speculations include genetic predisposition; however, the gene or genes responsible for this remain unidentified. The condition may have a hereditary basis. Other possible causes include elevated insulin production. Most cases of PCOS involve insulin resistance. It is thought that adipose tissue dysfunction plays a role in the insulin resistance seen in PCOS. Insulin can induce excess testosterone secretion from the ovaries. A complication associated with polycystic ovary syndrome is high cholesterol, which is treated with statins. In a meta-analysis, atorvastatin was shown to decrease androgen concentrations in people with hyperandrogenism.Elevated insulin leads to lower production of sex hormone binding globulin (SHBG), a regulatory glycoprotein that suppresses the function of androgens. High blood levels of insulin also work in conjunction with ovarian sensitivity to insulin to cause hyperandrogenemia, the primary symptom of PCOS. Obese individuals may be more biologically inclined to PCOS due to markedly higher insulin. This hormonal imbalance can lead to chronic anovulation, in which the ovaries fail to release mature eggs. These cases of ovulatory dysfunction are linked to infertility and menstrual disturbances. A post hoc analysis from a randomized, placebo-controlled, multi-centre study carried out at 11 secondary care centres, as well as a longitudinal single-centre study on pregnant women in Norway, also determined that metformin had no effect on maternal androgens in pregnancies occurring in the setting of PCOS.One systemic review suggested that polymorphisms in the vitamin D receptor gene are associated with the prognosis of polycystic ovary syndrome, though this is based on small sample sizes and is debated. Studies have shown benefits for vitamin D supplementation in women with vitamin D deficiency and PCOS.Hyperinsulinemia can increase the production of androgens in the ovaries. One context in which this occurs is HAIR-AN syndrome, a rare subtype of PCOS. Hyperthecosis and hyperinsulinemia Hyperthecosis occurs when the cells of the ovarian stroma transition from interstitial cells, located between other cells, into luteinized theca cells. Theca cells are located in the ovarian follicles and become luteinized when the ovarian follicle bursts and a new corpus luteum is formed. The dispersal of luteinized theca cells throughout the ovarian stroma — in contrast to their distribution in PCOS, in which luteinized theca cells occur around cystic follicles only — causes women with hyperthecosis to have higher testosterone levels and virilization) than women with PCOS. Elevated insulin is also characteristic of hyperthecosis. Hyperthecosis most commonly develops in postmenopausal women and is linked to acne, hirsutism, growth of the clitoris, baldness, and voice deepening.Obesity can play a role in insulin resistance. It makes thecal cells more responsive to luteinizing hormone. Therefore, obesity increases ovarian androgen production. Additionally, obesity elevates inflammatory adipokines which leads to not only adipogenesis, but also heightened insulin resistance. Cushing’s syndrome Cushings syndrome develops as a result of long-term exposure to the hormone cortisol. Cushings syndrome can either be exogenous or endogenous, depending on whether it is caused by an external or internal source, respectively. The intake of glucocorticoids, a type of corticosteroid, is a common cause for the development of exogenous Cushings syndrome. Endogenous Cushings syndrome can occur when the body produces excess cortisol. This occurs when the hypothalamus of the brain signals to the pituitary gland with excess corticotropin-releasing hormone, which in turn secretes adrenocorticotropin hormone (ACTH). ACTH then causes the adrenal glands to release cortisol into the blood. Signs of Cushings syndrome include muscle weakness, easy bruising, weight gain, male-pattern hair growth (hirsutism), coloured stretch marks, and an excessively reddish complexion in the face. Cushings syndrome can cause androgen excess and hence the signs and symptoms of hyperandrogenism. Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders that cause a lack of an enzyme necessary for the production of cortisol and/or aldosterone, steroid hormones produced by the adrenal cortex. Most cases of CAH are due to 21-hydroxylase deficiencies. The heightened androgen levels seen in congenital adrenal hyperplasia affect the hypothalamic–pituitary–gonadal axis. Heightened androgen levels can also affect the ovaries, which can lead to infertility as well as chronic anovulation.Since CAH consists of multiple disorders, the signs, symptoms and severity of hyperandrogenism may stem from a variety of specific mutations. Genotyping is therefore critical to verify diagnoses and to establish prognostic factors for individuals. Genotyping is also crucial for people seeking to use genetic counselling as an aid to family planning.In women, CAH causes ambiguous genitals at birth and excessive pubic hair, enlargement of the clitoris, and hirsutism in adolescence. Although CAH causes rapid growth in childhood, adult women with CAH are shorter than average due to early puberty and closure of the growth plates in the long bones. Symptoms in males include early showings of pubic hair, enlargement of the penis, and rapid musculoskeletal growth. Tumors Adrenocortical carcinoma and tumors Adrenocortical carcinoma occurs rarely; the average incidence rate is estimated to be 1–2 cases per million annually. The disease involves the formation of cancerous cells within the cortex of one or both of the adrenal glands. Although these tumors are identified in fewer than two percent of patients diagnosed with hyperandrogenism, the possibility must be considered within this population. In one study, more than half of tumor-affected patients had elevated levels of the androgens androstenedione, dehydroepiandrosterone sulfate, and testosterone. The elevation of androgens caused by adrenocortical carcinomas often causes patients to develop Cushings syndrome, primary aldosteronism, and hyperandrogenism. The molecular basis of the disease has yet to be elucidated. Adenoma of the adrenal gland Adrenal adenomas are benign tumors of the adrenal gland. In most cases, the tumors display no symptoms and require no treatment. In rare cases, however, some adrenal adenomas may become activated. When activated, the adenoma begins to produce hormones in much larger quantities than what the adrenal glands would normally produce, leading to health complications including primary aldosteronism and hyperandrogenism. Arrhenoblastoma Arrhenoblastoma is an uncommon tumor of the ovary. It is composed of sterol cells, Leydig cells, or some combination of the two. The tumor can produce male or female hormones and may cause masculinization. In a prepubescent child, a tumor may cause precocious puberty. Malignant arrhenoblastoma accounts for 30% of cases of arrhenoblastoma, the other 70% being largely benign and curable with surgery. Hilar cell tumor A hilar cell tumor is an androgen-producing ovarian tumor that is most commonly found in older women and often leads to the development of male sex characteristics. The tumor tends to occur around the region of the ovary where the blood vessels enter the organ, known as the hilum. This type of tumor tends to be small in size and in most cases can be entirely removed and its symptoms reversed through surgery. Krukenberg tumor A Krukenberg tumor is a quickly developing malignant tumor found in one or both ovaries. In most cases, the tumor primarily originates from tissues in the stomach, pancreas, gallbladder, colon, or breast. It colonized the ovary by spreading through the peritoneal cavity. These tumors cause virilization. Increased androgen production due to elevations in human chorionic gonadotropin is hypothesized as the main cause of hyperandrogenism in people with Krukenberg tumors. Menopause The end of ovulation and the beginning of menopause can result in hyperandrogenism. During this transition, the body stops releasing estrogen at a faster rate than it stops releasing androgens. In some cases, the difference between the lower estrogen levels and higher androgen levels can produce hyperandrogenism. A decrease in sex hormone levels while the free androgen index increases can also contribute to this process. Drugs Many drugs can provoke symptoms of hyperandrogenism. These symptoms include, but are not limited to hirsutism, acne, dermatitis, androgenic alopecia, irregularities in menstruation, clitoral hypertrophy, and the deepening of the voice. Drugs most frequently implicated in hyperandrogenism include anabolic steroids, synthetic progestins, and antiepileptics; however, many other drugs may also cause hyperandrogenism. This can happen through one of five mechanisms: the direct introduction of androgens to the body, the binding of the drug to androgen receptors (as is the case with anabolic-androgenic steroids), a reduction of sex hormone-binding globulin plasma concentration that leads to an increase in free testosterone, interference with the hypothalamic–pituitary–ovarian (HPO) axis, or an increase in the release of adrenal androgens. Certain drugs cause hyperandrogenism through mechanisms that remain unclear. For example, the molecular basis by which valproate induces hyperandrogenism and polycystic ovary syndrome has yet to be determined. However, one study showed that women taking valproic acid had higher testosterone levels and incidences of hyperandrogenism compared to women who were not taking valproic acid. Heredity Hyperandrogenism can appear as a symptom of many different genetic and medical conditions. Some of the conditions with hyperandrogenic symptoms, including PCOS, may sometimes be hereditary. Additionally, it is thought that epigenetics may contribute to the pathogenesis of polycystic ovary syndrome.One potential cause of PCOS is maternal hyperandrogenism, whereby hormonal irregularities in the mother can affect the development of the child during gestation, resulting in the passing of polycystic ovary syndrome from mother to child. However, no androgen elevations in were found in the umbilical cord blood of children born to mothers with PCOS. Diagnosis Diagnosing hyperandrogenism can be complex due to the wide variety and severity of signs and symptoms that may present. It is most often diagnosed by checking for signs of hirsutism according to a standardized method that scores the range of excess hair growth.Girls may show symptoms of hyperandrogenism early in life, but physicians become more concerned when the patient is in her late teens or older.Checking medical history and a physical examination of symptoms are used for an initial diagnosis. Patient history assessed includes age at thelarche, adrenarche, and menarche; patterns of menstruation; obesity; reproductive history; and the start and advancement of hyperandrogenism symptoms. Patterns of menstruation are examined since irregular patterns may accompany hyperandrogenism. Other conditions that may present alongside hirsutism that can contribute to diagnosis include androgenic alopecia and acne. If hyperandrogenism is severe, virilization may occur.Family history is also assessed for occurrences of hyperandrogenism symptoms or obesity in other family members.Laboratory tests can measure FSH, luteininzing hormone, DHEAS, prolactin, 17α-hydroxyprogesterone, and total and free testosterone in the blood. Abnormally high levels of any of these hormones help in diagnosing hyperandrogenism. Prevention Since risk factors are not known and vary among individuals with hyperandrogenism, there is no sure method to prevent the condition. Accordingly, more long-term studies are needed to find a cause of the condition before a sufficient method of prevention can be established.Despite this, there are a few things that can help avoid long-term medical issues related to hyperandrogenism and PCOS. Getting checked by a medical professional for hyperandrogenism — especially if one has a family history of the condition, irregular periods, or diabetes — can be beneficial. A healthy weight and diet may reduce the chances, as continued exercise and a healthy diet lead to an improved menstrual cycle, decreased insulin levels, and lowered androgen concentrations. Treatment There is no definitive treatment for hyperandrogenism as it varies with the underlying condition that causes it. As a hormonal symptom of PCOS, menopause, and other endocrine conditions, it is primarily treated as a symptom of these conditions. Drugs may be considered only in women who do not plan on becoming pregnant in the near future. Some effective drugs for facial hirsutism includes eflornithine, which may cause birth defects in pregnant women. Retinoids and antibiotics can be used for acne and minoxidil for alopecia. Systemically, it is treated with antiandrogens such as cyproterone acetate, flutamide and spironolactone to reduce androgenic signaling. For hyperandrogenism caused by late-onset congenital adrenal hyperplasia (LOCAH), treatment is primarily focused on providing the patient with glucocorticoids to combat the low cortisol production and the corresponding increase in androgens caused by the increase in size of the adrenal glands. Estrogen-based oral contraceptives are used to treat both LOCAH- and PCOS-associated hyperandrogenism. These hormonal treatments reduce the androgen excess and suppress adrenal androgen production, bringing about a significant decrease in hirsutism.Hyperandrogenism is often managed symptomatically. Hirsutism and acne both respond well to the hormonal treatments described above, with 60–100% of patients reporting an improvement in hirsutism. Androgenic alopecia however, does not show an improvement with hormonal treatments and requires other treatments, such as hair transplantation.Supplementation can also contribute to the managing the symptomatic effects of hyperandrogenism. In a meta-analysis, high-dose vitamin D supplements given to women with vitamin D deficiency due to PCOS improved glucose levels, insulin sensitivity, and cholesterol levels, as well as lowering testosterone, sex hormone-binding globulin, and the free androgen index, all of which are associated with hyperandrogenism. Vitamin D supplementation in women with vitamin D deficiency but without PCOS did not show the same results. Targeting insulin resistance and obesity Lifestyle modifications are the first-line treatment for PCOS. They help improve body composition, insulin resistance, and hyperandrogenism. However, it is unclear whether they help improve mood, quality of life, and reproductive outcomes. A meta-analysis study in 2017 showed that bariatric surgery in women with severe obesity and PCOS decreased levels of total and free testosterone and helped correct hirsutism and menstrual dysfunction.Insulin resistance in women with PCOS is typically treated with insulin-sensitizer drugs such as metformin. Metformin can help to decrease weight and androgen levels. When combined with lifestyle modifications (changes in diet and exercise), it has been linked with lower body mass index and a reduction in menstrual problems. However, the use of metformin in women with PCOS should only be considered in patients with impaired glucose tolerance. Society and culture Because androgen excess is manifested in noticeable physical features (such as hirsutism), social stigma may be associated with it. Sports Current evidence-based studies show that unusually high levels of circulating testosterone are associated with increased athletic performance in women, unless they lack androgen sensitivity. However, controversy has emerged in the form of the claim that testosterone is not unlike any other physical parameter with reference to bestowing advantages or disadvantages on female athletes. Existing regulations throughout competitive sports are currently being refined to specifically address this particular claim. Following the case of South African athlete Caster Semenya, an athlete with a difference in sex development (DSD), the International Association of Athletics Federations introduced its hyperandrogenism regulations, which restricted women with high testosterone levels, whether the hormones were produced by ovaries, adrenals, or testes. These regulations replaced the earlier sex verification rules.Following a series of legal challenges, regulations called the Eligibility Regulations for the Female Classification (Athletes with Differences of Sexual Development) were released on 1 May 2019. These regulations apply only to athletes who have a DSD, high testosterone and virilization, and no longer include hyperandrogenism from non-DSD-related causes such as PCOS. Such DSDs, often seen in people who have a Y chromosome and testes, include 5α‐reductase deficiency, partial androgen insensitivity, and congenital adrenal hyperplasia. Social definition Cultural variation can define hyperandrogenism socially—apart from clinical and chemical definitions—to make some hair growth unacceptable even if it is considered clinically normal based on metrics like the Ferriman-Gallwey score. For example, only pubic and axillary hair may be tolerated in North American women, while other androgen-dependent hair such as growth on the upper lip, over the linea alba, on the thighs, and around the areola is not. Organizations Professional organizations such as the Androgen Excess and PCOS Society exist to promote the research, treatment, diagnosis, and prevention of such disorders and to educate the public and scientific community about them. See also Hypoandrogenism Hypergonadism Hypergonadotropic hypergonadism Hypogonadism Hyperestrogenism Hypoestrogenism Androgen-dependent condition References == External links ==

Mucositis

Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (GI) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment.Oral and gastrointestinal (GI) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary tract mucositis increases mortality and morbidity and contributes to rising health care costs.For most cancer treatment, about 5–15% of patients get mucositis. However, with 5-fluorouracil (5-FU), up to 40% get mucositis, and 10–15% get grade 3–4 oral mucositis. Irinotecan is associated with severe GI mucositis in over 20% of patients. Seventy-five to eighty percent of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well.Radiotherapy to the head and neck or to the pelvis or abdomen is associated with Grade 3 and Grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to > 70% of patients in most trials. Oral mucositis is particularly profound and prolonged among HSCT recipients who receive total-body irradiation. Signs and symptoms Cancer patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks.As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish-white fibrin clot called a pseudomembrane. Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Oral mucositis can be severely painful. The degree of pain is usually related to the extent of the tissue damage. Pain is often described as a burning sensation accompanied by reddening. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth.Dysgeusia, or an alteration in taste perception, is common, especially for those who are receiving concomitant radiation therapy to the neck and mouth area. "Taste blindness", or an altered sense of taste, is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs. Common complaints are of food tasting too sweet or too bitter or of a continuous metallic taste. Complications Sores or ulcerations can become infected by virus, bacteria or fungus. Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicaemia (especially in immunosuppressed patients). Therefore, oral mucositis can be a dose-limiting condition, disrupting a patient’s optimal cancer treatment plan and consequentially decreasing their chances of survival. Pathophysiology The pathophysiology of mucositis is complex and multifactorial. Currently, Sonis five phase model is the accepted explanation for the process. The 5 stages are: Initiation phase. Free radicals are produced due to DNA damage caused by chemo- or radiotherapy. Primary damage response. Chemotherapy, radiotherapy and free radicals all contribute to the activation of transcription factors, such as NF-κB. This results in the upregulation of pro-inflammatory cytokines, ceramide, nitric oxide and matrix metalloproteinases. The consequence of this is mucosal destruction, caused by thinning of the epithelium due to tissue injury and cell death. Signal amplification. Positive or negative feedback loops involving some of the molecules in the previous phase can exacerbate or prolong tissue injury. For example, the pro-inflammatory cytokine TNF-α can positively feedback on NF-κB thus inducing more pro-inflammatory cytokine production. Ulceration. Bacteria colonise ulcers and their cell wall products infiltrate the submucosa. This leads to activation of tissue macrophages, which causes further production of pro-inflammatory cytokines. In addition, bacteria-mediated immune signalling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. Healing. Signalling from the extracellular matrix of the submucosa results in epithelial proliferation and differentiation, and thus a thickening of the epithelium. The local oral flora are reinstated. Diagnosis Diagnosis is based on the symptoms the patient is experiencing and the appearance of the tissues of the mouth following chemotherapy, bone marrow transplants or radiotherapy. Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis.The severity of oral mucositis can be evaluated using several different assessment tools. Two of the most commonly used are the World Health Organization (WHO) Oral Toxicity score and the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Oral Mucositis. While the NCI system has separate scores for appearance (erythema and ulceration) and function (pain and ability to eat solids, liquids, or nothing by mouth), the WHO score combines both elements into a single score that grades the severity of the condition from 0 (no oral mucositis) to 4 (swallowing not possible such that patient needs supplementary nutrition). Another scale developed in 1999, the Oral Mucositis Assessment Scale (OMAS) has been shown to be highly reproducible between observers, responsive over time, and accurate in recording symptoms associated with mucositis. The OMAS provides an objective assessment of oral mucositis based on assessment of the appearance and extent of redness and ulceration in various areas of the mouth. Prevention A 2015 Cochrane systematic review assessing the prevention of chemotherapy-induced oral mucositis concluded that oral cryotherapy leads to large reductions in the incidence of oral mucositis of all severities in adults receiving 5-FU treatment for solid cancers. The evidence also indicates a reduction of oral mucositis in adults receiving high-dose melphalan-based cancer treatment prior to haematopoietic stem cell transplantation, although there is uncertainty regarding the size of the reduction in this instance. No evidence was found for use of this preventive measure in children. Oral cryotherapy involves the placement of rounded ice chips in the mouth, which cools the oral tissues and causes vasoconstriction. This decreases blood flow to the region and, hence, also restricts the amounts of the chemotherapy drugs delivered to the tissues. Treatment Treatment of mucositis is mainly supportive. Oral hygiene is the mainstay of treatment; patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse.Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocaine for relief of pain. However, care should be taken as the high doses of viscous lidocaine my cause adverse effects. A study reported that lidocaine has a potential toxicity; when it was tested on patients with oral mucositis who underwent a bone marrow transplant, lidocaine anesthetic mouthwash was found to be systemically absorbed.Palifermin is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have been reported, including the use of cytokines and other modifiers of inflammation (e.g., IL-1, IL-11, TGF-beta3), amino acid supplementation (e.g., glutamine), vitamins, colony-stimulating factors, cryotherapy, and laser therapy.Symptomatic relief of the pain of oral mucositis may be provided by barrier protection agents such as concentrated oral gel products (e.g. Gelclair). Caphosol is a mouth rinse which has been shown to prevent and treat oral mucositis caused by radiation and high-dose chemotherapy. MuGard is a FDA-cleared mucoadhesive oral protectant, developed by Access Pharmaceuticals, Inc., that is designed to form a protective hydrogel coating over the oral mucosa while a patient is undergoing chemotherapy and/or radiotherapy cancer treatments to the head and neck. Additionally, the efficacy of MuGard for the prevention or treatment of mucositis has been tested by a prospective, randomized clinical trial in which 43% of head and neck cancer patients using MuGard prophylactically never got oral mucositis. NeutraSal is an FDA-cleared calcium phosphate mouth rinse that has been shown in an open-label, observational registry trial to prevent and reduce the severity of oral mucositis caused by radiation and high-dose chemotherapy. In the trial, 56% of the radiotherapy patients reported 0 (WHO score) or no mucositis, which is significantly lower than historical rates. Another super saturated calcium phosphate rinse on the market and cleared by the FDA is the US based SalivaMAX. The Mayo Clinic has been testing the antidepressant doxepin in a mouthwash to help treat symptoms.In 2011, the FDA cleared episil oral liquid for the management and relief of pain of oral lesions with various etiologies, including oral mucositis/stomatitis which may be caused by chemotherapy or radiation therapy. The transformative mechanism of action of episil creates a lipid membrane that mechanically bonds to the oral cavity mucosa to coat and soothe inflammation and ulcerations, and blanket painful lesions. In a multicenter, randomized, double-blind, single-dose study involving 38 head and neck cancer patients with oral mucositis (WHO grades 2-3) undergoing radiation therapy, episil clinically demonstrated fast-acting relief that lasted up to 8 hours. Episil oral liquid is marketed in the US by Cangene. In a 2012 randomized controlled pilot study involving pediatric patients, topical application of honey was found to reduce recovery time compared to benzocaine gel in grade 2 and 3 chemotherapy-induced oral mucositis to a degree that was statistically significant. In grade 3 oral mucositis, honey was as effective as a mixture of honey, olive oil and propolis, while both treatments were found to reduce recovery time compared to the benzocaine control.Clinical research is ongoing in oral mucositis. A recent phase 2 exploratory trial in oral mucositis reported that dusquetide, a unique innate immune modulator with a mechanism that potentially addresses each of the phases of OM pathophysiology, is able to reduce the duration of severe oral mucositis, as well as reducing the incidence of infection See also Stomatitis References General sources Mucositis Resource Center of the MASCC/ISOO Mucositis Study Group. Medical journal articles, guidelines, recommendations, and slides and videos from conference presentations. == External links ==

Hermansky–Pudlak syndrome

Heřmanský–Pudlák syndrome (often written Hermansky–Pudlak syndrome or abbreviated HPS) is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism (decreased pigmentation), bleeding problems due to a platelet abnormality (platelet storage pool defect), and storage of an abnormal fat-protein compound (lysosomal accumulation of ceroid lipofuscin). It is considered to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico. There are eight classic forms of the disorder, based on the genetic mutation from which the disorder stems. Signs and symptoms There are three main disorders caused by Hermansky–Pudlak syndrome, which result in these symptoms: Albinism and eye problems: Individuals will have varying amounts of skin pigment (melanin). Because of the albinism there are eye problems such as light sensitivity (photophobia), strabismus (crossed eyes), and nystagmus (involuntary eye movements). Hermansky–Pudlak syndrome also impairs vision. Bleeding disorders: Individuals with the syndrome have platelet dysfunction. Since platelets are necessary for blood clotting, individuals will bruise and bleed easily. Cellular storage disorders: The syndrome causes a wax-like substance (ceroid) to accumulate in the body tissues and cause damage, especially in the lungs and kidneys.It is also associated with granulomatous colitis,, an inflammation of the colon, and with pulmonary fibrosis, a potentially fatal lung disease. Causes HPS can be caused by mutations in several genes: HPS1, HPS3, HPS4, HPS5, HPS6 and HPS7.HPS type 2, which includes immunodeficiency in its phenotype, is caused by mutation in the AP3B1 gene.HPS type 7 may result from a mutation in the gene coding for dysbindin protein.Hermansky–Pudlak syndrome is thought to be inherited as an autosomal recessive genetic trait. The defective gene, called HSP, responsible for this disorder is located on the long arm of chromosome 10 (10q2). Some research suggests that an abnormality of lysosomal function may be responsible for the development of the disease. HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1 and Biogenesis of Lysosome-related Organelles Complex (BLOC1, BLOC1S2 and BLOC3) are associated with Hermansky–Pudlak syndrome.In autosomal recessive disorders, the condition does not appear unless a person inherits two copies of the defective gene responsible for the disorder, one copy coming from each parent. If an individual receives one normal gene and one gene for the disorder, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. Pathophysiology The mechanism of Hermansky–Pudlak syndrome indicates that platelets in affected individuals accumulate abnormally with thrombin, epinephrine, and adenosine diphosphate, furthermore platelets in these individuals have a lower amount of dense bodies Diagnosis The diagnosis of HPS is established by clinical findings of hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absent dense bodies on whole mount electron microscopy of platelets. Molecular genetic testing of the HPS1 gene is available on a clinical basis for individuals from northwestern Puerto Rico. Molecular testing of the HPS3 gene is available on a clinical basis for individuals of central Puerto Rican or Ashkenazi Jewish heritage. Sequence analysis is available on a clinical basis for mutations in HPS1 and HPS4. Diagnosis of individuals with other types of HPS is available on a research basis only. Treatment While there is no cure for HPS, treatment for chronic hemorrhages associated with the disorder includes therapy with vitamin E and the antidiuretic dDAVP. Considerations for patients A preoperative pulmonology consultation is needed. The anesthesia team should be aware that patients may have postoperative pulmonary complications as part of the syndrome.Preoperative hematology consultation is advisable prior to elective ocular surgeries. Since patients with the syndrome have bleeding tendencies, intraoperative, perioperative, and postoperative hemorrhages should be prevented and treated. If platelet aggregation improves with desmopressin, it may be administered in the preoperative period. However, sometimes plasmapheresis is needed in the perioperative period.Ophthalmologists should try to avoid retrobulbar blocks in patients with the syndrome. Whenever possible, patients with HPS may benefit from general endotracheal anesthesia. Phacoemulsification may help prevent intraoperative and postoperative bleeding in patients with the syndrome. Prolonged bleeding has been reported following strabismus surgery in patients with the syndrome. Prognosis The course of HPS has been mild in rare instances of the disorder, however, the general prognosis is still considered to be poor.The disease can cause dysfunctions of the lungs, intestine, kidneys, and heart. The major complication of most forms of the disorder is pulmonary fibrosis, which typically exhibits in patients ages 40–50 years. This is a fatal complication seen in many forms of HPS, and is the usual cause of death from the disorder. HPS patients who develop pulmonary fibrosis typically have type 1 or type 4. Research HPS is one of the rare lung diseases currently being studied by The Rare Lung Diseases Consortium (RLDC). The RLDC is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), of the National Center for Advancing Translational Sciences (NCATS). The RLDC is dedicated to developing new diagnostics and therapeutics for patients with rare lung diseases, through collaboration between the NIH, patient organizations and clinical investigators. Eponym It is named for František Heřmanský (1916–1980) and Pavel Pudlák (1927–1993). See also Biogenesis of lysosome-related organelles complex 1 List of cutaneous conditions References External links GeneReviews/NCBI/NIH/UW entry on Hermansky-Pudlak Syndrome